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1.
BMC Bioinformatics ; 20(1): 450, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477009

RESUMO

BACKGROUND: Mutational signatures are specific patterns of somatic mutations introduced into the genome by oncogenic processes. Several mutational signatures have been identified and quantified from multiple cancer studies, and some of them have been linked to known oncogenic processes. Identification of the processes contributing to mutations observed in a sample is potentially informative to understand the cancer etiology. RESULTS: We present here SigsPack, a Bioconductor package to estimate a sample's exposure to mutational processes described by a set of mutational signatures. The package also provides functions to estimate stability of these exposures, using bootstrapping. The performance of exposure and exposure stability estimations have been validated using synthetic and real data. Finally, the package provides tools to normalize the mutation frequencies with respect to the tri-nucleotide contents of the regions probed in the experiment. The importance of this effect is illustrated in an example. CONCLUSION: SigsPack provides a complete set of tools for individual sample exposure estimation, and for mutation catalogue & mutational signatures normalization.


Assuntos
Carcinogênese/genética , Genoma Humano , Mutação , Proteínas de Neoplasias/genética , Neoplasias/genética , Software , Carcinogênese/patologia , Análise Mutacional de DNA , Humanos , Taxa de Mutação , Neoplasias/patologia
2.
BMC Evol Biol ; 19(1): 172, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31443631

RESUMO

BACKGROUND: The evolution of multi-cellular animals has produced a conspicuous trend toward increased body size. This trend has introduced at least two novel problems: an expected elevated risk of somatic disorders, such as cancer, and declining evolvability due to generally reduced population size, lower reproduction rate and extended generation time. Low population size is widely recognized to explain the high mutation rates in animals by limiting the presumed universally negative selection acting on mutation rates. RESULTS: Here, we present evidence from stochastic modeling that the direction and strength of selection acting on mutation rates is highly dependent on the evolution of somatic maintenance, and thus longevity, which modulates the cost of somatic mutations. CONCLUSIONS: We argue that the impact of the evolution of longevity on mutation rates may have been critical in facilitating animal evolution.


Assuntos
Evolução Biológica , Tamanho Corporal , Modelos Genéticos , Taxa de Mutação , Animais , Simulação por Computador , Longevidade , Método de Monte Carlo , Mutação , Neoplasias/genética , Fenótipo , Densidade Demográfica , Seleção Genética
3.
BMC Evol Biol ; 19(1): 170, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412772

RESUMO

BACKGROUND: In the absence of sex and recombination, genomes are expected to accumulate deleterious mutations via an irreversible process known as Muller's ratchet, especially in the case of polyploidy. In contrast, no genome-wide mutation accumulation was detected in a transcriptome of facultative apomictic, hexaploid plants of the Ranunculus auricomus complex. We hypothesize that mutations cannot accumulate in flowering plants with facultative sexuality because sexual and asexual development concurrently occurs within the same generation. We assume a strong effect of purging selection on reduced gametophytes in the sexual developmental pathway because previously masked recessive deleterious mutations would be exposed to selection. RESULTS: We test this hypothesis by modeling mutation elimination using apomictic hexaploid plants of the R. auricomus complex. To estimate mean recombination rates, the mean number of recombinants per generation was calculated by genotyping three F1 progeny arrays with six microsatellite markers and character incompatibility analyses. We estimated the strength of purging selection in gametophytes by calculating abortion rates of sexual versus apomictic development at the female gametophyte, seed and offspring stage. Accordingly, we applied three selection coefficients by considering effects of purging selection against mutations on (1) male and female gametophytes in the sexual pathway (additive, s = 1.000), (2) female gametophytes only (s = 0.520), and (3) on adult plants only (sporophytes, s = 0.212). We implemented recombination rates into a mathematical model considering the three different selection coefficients, and a genomic mutation rate calculated from genome size of our plants and plant-specific mutation rates. We revealed a mean of 6.05% recombinants per generation. This recombination rate eliminates mutations after 138, 204 or 246 generations, depending on the respective selection coefficients (s = 1.000, 0.520, and 0.212). CONCLUSIONS: Our results confirm that the empirically observed frequencies of facultative recombination suffice to prevent accumulation of deleterious mutations via Muller's ratchet even in a polyploid genome. The efficiency of selection is in flowering plants strongly increased by acting on the haplontic (reduced) gametophyte stage.


Assuntos
Acúmulo de Mutações , Ranunculus/genética , Recombinação Genética , DNA de Plantas/análise , DNA de Plantas/genética , Repetições de Microssatélites , Taxa de Mutação , Óvulo Vegetal , Poliploidia , Ranunculus/crescimento & desenvolvimento , Ranunculus/fisiologia , Reprodução Assexuada
4.
BMC Evol Biol ; 19(1): 175, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462290

RESUMO

BACKGROUND: Organisms are expected to respond to changing environmental conditions through local adaptation, range shift or local extinction. The process of local adaptation can occur by genetic changes or phenotypic plasticity, and becomes especially relevant when dispersal abilities or possibilities are somehow constrained. For genetic changes to occur, mutations are the ultimate source of variation and the mutation rate in terms of a mutator locus can be subject to evolutionary change. Recent findings suggest that the evolution of the mutation rate in a sexual species can advance invasion speed and promote adaptation to novel environmental conditions. Following this idea, this work uses an individual-based model approach to investigate if the mutation rate can also evolve in a sexual species experiencing different conditions of directional climate change, under different scenarios of colored stochastic environmental noise, probability of recombination and of beneficial mutations. The color of the noise mimicked investigating the evolutionary dynamics of the mutation rate in different habitats. RESULTS: The results suggest that the mutation rate in a sexual species experiencing directional climate change scenarios can evolve and reach relatively high values mainly under conditions of complete linkage of the mutator locus and the adaptation locus. In contrast, when they are unlinked, the mutation rate can slightly increase only under scenarios where at least 50% of arising mutations are beneficial and the rate of environmental change is relatively fast. This result is robust under different scenarios of stochastic environmental noise, which supports the observation of no systematic variation in the mutation rate among organisms experiencing different habitats. CONCLUSIONS: Given that 50% beneficial mutations may be an unrealistic assumption, and that recombination is ubiquitous in sexual species, the evolution of an elevated mutation rate in a sexual species experiencing directional climate change might be rather unlikely. Furthermore, when the percentage of beneficial mutations and the population size are small, sexual species (especially multicellular ones) producing few offspring may be expected to react to changing environments not by adaptive genetic change, but mainly through plasticity. Without the ability for a plastic response, such species may become - at least locally - extinct.


Assuntos
Mudança Climática , Taxa de Mutação , Adaptação Fisiológica , Evolução Biológica , Simulação por Computador , Ecossistema , Extinção Biológica , Mutação , Densidade Demográfica , Reprodução
5.
Nat Commun ; 10(1): 3101, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308377

RESUMO

The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy.


Assuntos
Adenocarcinoma/genética , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Esofágicas/genética , Perfilação da Expressão Gênica/métodos , Medicina de Precisão/métodos , Antineoplásicos/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Biologia Computacional/métodos , Conjuntos de Dados como Assunto , Progressão da Doença , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Instabilidade Genômica , Humanos , Aprendizado de Máquina , Modelos Genéticos , Família Multigênica/efeitos dos fármacos , Taxa de Mutação , Polimorfismo de Nucleotídeo Único
6.
Nat Commun ; 10(1): 3090, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300647

RESUMO

The role of brain somatic mutations in Alzheimer's disease (AD) is not well understood. Here, we perform deep whole-exome sequencing (average read depth 584×) in 111 postmortem hippocampal formation and matched blood samples from 52 patients with AD and 11 individuals not affected by AD. The number of somatic single nucleotide variations (SNVs) in AD brain specimens increases significantly with aging, and the rate of mutation accumulation in the brain is 4.8-fold slower than that in AD blood. The putatively pathogenic brain somatic mutations identified in 26.9% (14 of 52) of AD individuals are enriched in PI3K-AKT, MAPK, and AMPK pathway genes known to contribute to hyperphosphorylation of tau. We show that a pathogenic brain somatic mutation in PIN1 leads to a loss-of-function mutation. In vitro mimicking of haploinsufficiency of PIN1 aberrantly increases tau phosphorylation and aggregation. This study provides new insights into the genetic architecture underlying the pathogenesis of AD.


Assuntos
Doença de Alzheimer/genética , Peptidilprolil Isomerase de Interação com NIMA/genética , Agregação Patológica de Proteínas/genética , Proteínas tau/metabolismo , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Doença de Alzheimer/patologia , Animais , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Haploinsuficiência , Hipocampo/citologia , Hipocampo/patologia , Humanos , Mutação com Perda de Função , Masculino , Camundongos , Pessoa de Meia-Idade , Taxa de Mutação , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Neurônios , Fosforilação/genética , Polimorfismo de Nucleotídeo Único , Agregação Patológica de Proteínas/patologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sequenciamento Completo do Exoma
7.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(3): 657-663, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31204914

RESUMO

OBJECTIVE: To study the instability of mitochondrial DNA(mt DNA) D-loop region genes in patients with Leukemia. METHODS: The HV-1 and HV-2 regions of D-loop region in 24 patients with leukemia were amplificated and sequenced, then their results were compared with revised Cambridge reference sequence (rCRS) and Databank mtDB. The mutation rate was detected by SPSS 22.0 statistics software. RESULTS: The total mutation rate in patients was 95.83% (23/24), the detection showed 82 mutated genes, out of which 47 (57.32%) mutated genes located in HV-1 region, 35 (42.68%) mutated genes in HV-2 region. The comparison showed that the mutation rate in untreated (UT) group and treated (T) group of AML patients was (2.37±0.82)×10-3 and (4.76±2.45)×10-3 respectively(P<0.01), the mutation rate in PR and CR groups of treated AML patients was (5.10±2.56)×10-3 and (4.51±2.51)×10-3 respectively (P<0.05), the comparison among M3 group showed that the mutation rates in UT, PR and CR groups were (2.55±0.63)×10-3, (5.37±3.41)×10-3 and (3.71±1.65)×10-3 respectively (P>0.05). CONCLUSION: The more high mutation rate and many kinds of mutation types exist in D-loop region, suggesting that the genes in D-loop region display the more strong instability, the chemotherapy may aggravate the instability of genes in D-loop region.


Assuntos
DNA Mitocondrial , Leucemia , Humanos , Mitocôndrias , Mutação , Taxa de Mutação
8.
Gastroenterology ; 157(4): 1123-1137.e22, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31175866

RESUMO

BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis. METHODS: We microdissected neoplastic tissues from 6-24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations. RESULTS: We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis. CONCLUSIONS: In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer.


Assuntos
Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/genética , Mutação , Neoplasias Intraductais Pancreáticas/genética , Neoplasias Pancreáticas/genética , Idoso , Idoso de 80 Anos ou mais , Transformação Celular Neoplásica/patologia , Cromograninas/genética , Evolução Clonal , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Evolução Molecular , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Estadiamento de Neoplasias , Proteínas Oncogênicas/genética , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Pancreáticas/patologia , Fenótipo , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos Retrospectivos
9.
Lancet Haematol ; 6(5): e276-e284, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31036317

RESUMO

BACKGROUND: Kinase domain mutations in BCR-ABL1 are associated with resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukaemia. Next-generation sequencing (NGS) allows detection of low-level kinase domain mutations, but its relevance in clinical practice remains debated. We aimed to examine the clinical effects of low-level kinase domain mutations identified using NGS in patients with chronic myeloid leukaemia. METHODS: In this population-based study, we included consecutive patients newly diagnosed with chronic myeloid leukaemia treated with first-line tyrosine kinase inhibitors, and patients identified at the time of resistance to first-line treatment with imatinib at six institutions (teaching hospitals and district hospitals) in southeast England. We screened patients for BCR-ABL1 kinase domain mutations using NGS, irrespective of patient response to tyrosine kinase inhibitor therapy. When we detected a mutation with NGS, we retrospectively analysed all previous samples to establish the date of first occurrence and subsequent kinetics of the mutant subclone (or subclones). The primary endpoints of this study were progression-free and event-free survival at 5 years. FINDINGS: Between Feb 1, 2007, and Dec 31, 2014, we screened 121 patients with chronic myeloid leukaemia for BCR-ABL1 kinase domain mutation. 99 consecutive patients were newly diagnosed, with available sequential RNA stored. The remaining 22 patients were diagnosed between June 1, 1999, and June 30, 2006, and were screened at the time of resistance to first-line treatment with imatinib. Imatinib was the first-line treatment for 111 patients, nilotinib for seven patients, and dasatinib for three patients. We detected a kinase domain mutation in 25 (21%) of 121 patients. Low-level kinase domain mutations were first identified in 17 (68%) of 25 patients with mutation. For patients with a complete cytogenetic response, 13 (14%) of 93 patients screened had a mutation. Five (71%) of the seven patients with a clinically relevant mutation lost complete cytogenetic response compared with 15 (17%) of 86 patients without a clinically relevant mutation (80 patients without mutation and six patients with a tyrosine kinase inhibitor-sensitive mutation, p=0·0031). Patients harbouring a mutant clone had poorer 5-year progression-free survival (65·3% [95% CI 40·5-81·8] vs 86·9% [75·8-93·2]; p=0·0161) and poorer 5-year event-free survival (22·2% [CI 5·6-45·9] vs 62·0% [50·4-71·6]; p<0·0001) than did patients without a mutation. We identified a kinase domain mutation in four (10%) of 41 patients with samples available at 3 months after starting first-line tyrosine kinase inhibitor treatment; all four subsequently progressed to accelerated phase disease compared with only three (8%) of 37 without a mutation (p<0·0001). INTERPRETATION: NGS reliably and consistently detected early appearance of kinase domain mutations that would not otherwise be detected by Sanger sequencing. For the first time, to our knowledge, we report the presence of kinase domain mutations after only 3 months of therapy, which could have substantial clinical implications. NGS will allow early clinical intervention and our findings will contribute to the establishment of new recommendations on the frequency of kinase domain mutation analysis to improve patient clinical care. FUNDING: None.


Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Domínios Proteicos/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Vigilância da População , Prognóstico , Resultado do Tratamento , Adulto Jovem
10.
BMC Evol Biol ; 19(1): 102, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088346

RESUMO

BACKGROUND: The S100A7 gene, also called psoriasin, was first described as an upregulated protein in psoriatic skin. For the past years, the importance of this protein as a key effector of innate immunity has been clearly established, not only due to its importance protecting against bacteria skin insult in humans, but also because of its important role in amplifying inflammatory processes. Given the importance of S100A7 in host defense, S100A7 genes have been mostly studied in humans. Here we provide a detailed analysis of the evolution of the gene family encoding for the S100A7 protein in mammals. RESULTS: Examination of several mammalian genomes revealed an unexpected variation in the copy number of S100A7. Among the most representative mammalian groups, we report that multiple events of duplication, gene loss and high mutation rates are shaping the evolution of this gene family. An unexpected result comes from Myotis species (order Chiroptera), where we found an outstanding S100A7 gene radiation, resulting in more than 10 copies in M. lucifugus and 5 copies in M. brandtii. These findings suggest a unique adaptive road in these species and are suggestive of special role of this protein in their immune system. CONCLUSIONS: We found different evolutionary histories among different mammalian groups. Overall, our results suggest that this gene family is evolving under the birth-and-death model of evolution. To our knowledge, this work represents the first detailed analysis of phylogenetic relationships of S100A7 within mammals and therefore will pave the way to further clarify their unique function in the immune system.


Assuntos
Quirópteros/genética , Evolução Molecular , Proteína A7 Ligante de Cálcio S100/genética , Sequência de Aminoácidos , Animais , Loci Gênicos , Taxa de Mutação , Filogenia , Recombinação Genética/genética , Proteína A7 Ligante de Cálcio S100/química
11.
Medicine (Baltimore) ; 98(22): e15811, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31145313

RESUMO

Immunoglobulin heavy chain variable region (IGHV) gene mutation status is a biomarker for the prognosis of chronic lymphocytic leukemia, whether it is associated with the diagnosis, staging, and prognosis of patients with mantle cell lymphoma (MCL) remains to be determined.The IGHV gene mutations of 52 MCL patients were determined by DNA sequencing and compared with published IGHV germline sequences.DNA sequence alignment of IGHV variable regions with published IGHV germline sequences showed that the coincidence rate was 94% to 100%. Ten cases (21%) were significantly mutated with the rate of 96.9% to 94.0%. The overall survival time of patients was negatively correlated with the degree of IGHV gene mutation. Further survival analysis with log-rank test demonstrated that the patients with significant IGHV gene mutations showed a trend towards poor survival.The mutation rate of the IGHV variant region may be determined to assess the prognosis and overall survival time of MCL patients.


Assuntos
Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/mortalidade , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Feminino , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Análise de Sobrevida
12.
Forensic Sci Int Genet ; 41: 137-144, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31082622

RESUMO

Haplotyping of Y-chromosomal short tandem repeats (Y-STRs) reflects the paternal lineage, although, the father-son pair profiles may differ due to the germline mutations. In order to discriminate between closely related males in criminal cases, as well as for the correct application of Y-STRs in the paternity/kinship analysis and determination of the most recent common ancestor in the familial searching or genealogy research, the assessment of mutation rates of routinely used Y-STRs is of a great importance. We genotyped 120 males belonging to one wide deep-rooted pedigree separated by 1-20 meiosis. The haplotypes of analyzed males distributed over 12 different families (according to their surnames), with 113 originating from one ancestor, and the remaining 7 from the second, closely related to the previous one, belong to the R1b haplogroup. The analysis was performed using Powerplex® Y23 kit, Yfiler™ plus kit and 13 rapidly mutating (RM13) Y-STRs. In 20,855 allele transmissions, 175 mutations (61% repeat losses and 39% gains) and one gene conversion event were found at 25 out of 36 markers. The medians of locus-specific mutation rates estimated using the Bayesian approach ranged from 1.42 × 10-3 (95% credible interval (CI): 0.05 × 10-3 - 7.56 × 10-3) for loci with no observed mutations to 130.91 × 10-3 (95% CI: 102.91 × 10-3 - 162.78 × 10-3) for DYF399S1, with a median rate across all 36 markers of 10.06 × 10-3 (95% CI: 8.65 × 10-3 - 11.61 × 10-3). In 6349 male relative pairs, the 36 Y-STR set distinguished 98.4% relative pairs by at least one mutation, compared to 95.9%, 65.5% and 57.4% for RM13, Yfiler™ plus, and Powerplex® Y23 set, respectively. The extra-pair paternity rate was estimated at 11.9 × 10-3 (95% CI: 4.4 × 10-3 - 25.8 × 10-3) fitting within the range reported for some European populations. A significant positive correlation was observed between fathers' ages at the time of the Y chromosome transmission and mutability rates (R2 = 0.9495, p = 0.0256), with more significant results when analyzing RM markers (R2 = 0.9827, p = 0.0087).


Assuntos
Cromossomos Humanos Y , Repetições de Microssatélites , Taxa de Mutação , Linhagem , Impressões Digitais de DNA , Conjuntos de Dados como Assunto , Genótipo , Haplótipos , Humanos , Masculino , Sérvia
13.
Genome Biol Evol ; 11(6): 1663-1678, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31076752

RESUMO

The DNA replication timing program is modulated throughout development and is also one of the main factors influencing the distribution of mutation rates across the genome. However, the relationship between the mutagenic influence of replication timing and its developmental plasticity remains unexplored. Here, we studied the distribution of copy number variations (CNVs) and single nucleotide polymorphisms across the zebrafish genome in relation to changes in DNA replication timing during embryonic development in this model vertebrate species. We show that CNV sites exhibit strong replication timing plasticity during development, replicating significantly early during early development but significantly late during more advanced developmental stages. Reciprocally, genomic regions that changed their replication timing during development contained a higher proportion of CNVs than developmentally constant regions. Developmentally plastic CNV sites, in particular those that become delayed in their replication timing, were enriched for the clustered protocadherins, a set of genes important for neuronal development that have undergone extensive genetic and epigenetic diversification during zebrafish evolution. In contrast, single nucleotide polymorphism sites replicated consistently early throughout embryonic development, highlighting a unique aspect of the zebrafish genome. Our results uncover a hitherto unrecognized interface between development and evolution.


Assuntos
Replicação do DNA , Taxa de Mutação , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/genética , Animais , Variações do Número de Cópias de DNA , Embrião não Mamífero/metabolismo , Polimorfismo de Nucleotídeo Único , Fatores de Tempo , Peixe-Zebra/metabolismo
14.
J Dermatol ; 46(6): 507-514, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31038235

RESUMO

Skin adnexal cancers (SAC) are a heterogeneous group of rare malignancies with histological differentiation towards epithelial adnexa, which lack effective systemic treatments. The aim of this work is to identify any potentially druggable genomic alterations for possible targeted therapies. Cases of primary or recurrent/metastatic (RM) SAC between 2002 and 2014 were identified by searching the institutional cancer registration database. Histological sections of all referral cases were reviewed by a dedicated pathologist to confirm diagnosis. Immunohistochemistry was performed to assess the expression of androgen receptors (AR) and human epidermal growth factor receptor type 2 (HER2). Targeted next-generation sequencing (T-NGS) was performed to identify targetable mutations (panel of 50 genes analyzed by Cancer Hotspot Panel, Ion-Torrent Personal Genome Machine). Mutational analysis of the PTCH1 gene not present in the T-NGS panel was assessed by Sanger sequencing. A total of 45 cases with available histological samples were identified (35 primary, 10 RM). The most frequent histological type was porocarcinoma (n = 12). Globally, 14 cases (31%) were AR+ (6/10 RM, 60%; 8/35 primary, 23%). HER2 was shown as 2+ in eight of 42 (19%) cases (2/9 RM, 22%; 6/33 primary, 18%). DNA was adequate for T-NGS analysis in 25 cases. In the majority of cases (17 cases, 68%) at least one mutation in oncogenes or tumor suppressor genes was found: the most frequent ones involved TP.53 (13 cases, 76% of mutated SAC) and PIK3CA (three cases, 18%). The rate of PTCH1 mutation was 30%. These findings support the use of molecular screening in patients with advanced SAC.


Assuntos
Biomarcadores Tumorais/genética , Recidiva Local de Neoplasia/genética , Neoplasias de Anexos e de Apêndices Cutâneos/genética , Neoplasias das Glândulas Sebáceas/genética , Neoplasias das Glândulas Sudoríparas/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/genética , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Terapia de Alvo Molecular/métodos , Mutação , Taxa de Mutação , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Neoplasias de Anexos e de Apêndices Cutâneos/tratamento farmacológico , Neoplasias de Anexos e de Apêndices Cutâneos/patologia , Receptor Patched-1/antagonistas & inibidores , Receptor Patched-1/genética , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Estudos Retrospectivos , Neoplasias das Glândulas Sebáceas/tratamento farmacológico , Neoplasias das Glândulas Sebáceas/patologia , Neoplasias das Glândulas Sudoríparas/tratamento farmacológico , Neoplasias das Glândulas Sudoríparas/patologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética
15.
DNA Cell Biol ; 38(6): 541-548, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31140864

RESUMO

The aim of this research was to verify the mutation rate of the ring finger protein 43 (RNF43) of the transmembrane E3 ubiquitin ligase and investigate the influence of single nucleotide polymorphisms (SNPs) rs2257205 in RNF43 in a Chinese colorectal cancer (CRC) cohort. DNA from 177 diagnosed CRC patients' tissues or blood samples were extracted, amplified, and sequenced. Clinicopathological features, including age, gender, tumor location, tumor-lymph node-metastasis stage, and survival information, were analyzed. Four novel RNF43 mutations (including G659 and R117 sites) were validated in 177 CRC patients; all events were somatic frameshift mutations. Furthermore, we also found that an SNP (rs2257205) of the RNF43 X117 site was associated with overall survival (OS) instead of disease-free survival. G homozygote subjects were significantly correlated with poor OS compared with another group. Then we rescued RNF43 R117R (encoded by nucleotide CGC) and R117H (encoded by nucleotide CAC) expression in the HCT116 cells and analyzed the targets of the Wnt/ß-catenin pathway. The expression of CCND1 and c-Myc were decreased. The prognosis of CRC patients could be affected by the different functions of SNPs of RNF43.


Assuntos
Neoplasias Colorretais/mortalidade , Proteínas de Ligação a DNA/genética , Proteínas Oncogênicas/genética , Polimorfismo de Nucleotídeo Único , Idoso , Linhagem Celular Tumoral , China , Estudos de Coortes , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Prognóstico , Estudos Retrospectivos
16.
Virchows Arch ; 475(1): 39-47, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31056731

RESUMO

Our study was done in order to identify novel molecular markers to predict which locally advanced rectal cancers (LARCs) might be resistant to neoadjuvant chemoradiotherapy (nCRT). Seventy-four patients with LARCs treated with nCRT were collected. Pathological evaluation after nCRT was performed according to the tumor regression grading (TRG) system. Next-generation sequencing kit including 279 exons of 59 genes was performed on Illumina Miseq Platform. Sanger sequencing was performed to confirm some mutations. Four of the tumors (4/74, 5.4%) had BRAF mutation, which presented in one TRG 2 tumor and three TRG 3 tumors but was not observed in TRG 0-1 tumors. Higher mutational frequency of BRAF gene in TRG 3 tumors (3/12, 25%) was found in comparison with the TRG 0-2 tumors (1/62, 1.6%; p = 0.012). Eight tumors (8/74, 10.8%) harbored SMAD4 mutations, which was mutated across all TRG groups. However, SMAD4 mutated more in TRG 3 tumors (4/12, 33.3%) compared with that in TRG 0-2 tumors (4/62, 6.5%; p = 0.020). The patients with BRAF-mutated LARCs had shorter progression-free survival (PFS) (p = 0.045) and shorter overall survival (OS) (p = 0.000) than the BRAF wild-type (WT) ones. The patients with SMAD4-mutated tumors had shorter PFS than the WT cases (p = 0.008). BRAF and SMAD4 genetic mutations might be important molecular markers to predict resistance to nCRT and poor prognosis in LARCs. More cases are needed to confirm these findings in the near future.


Assuntos
Biomarcadores Tumorais/genética , Quimiorradioterapia Adjuvante , Resistencia a Medicamentos Antineoplásicos/genética , Mutação , Terapia Neoadjuvante , Proteínas Proto-Oncogênicas B-raf/genética , Tolerância a Radiação/genética , Neoplasias Retais/terapia , Proteína Smad4/genética , Adulto , Idoso , Quimiorradioterapia Adjuvante/efeitos adversos , Análise Mutacional de DNA , Progressão da Doença , Éxons , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Terapia Neoadjuvante/efeitos adversos , Gradação de Tumores , Estadiamento de Neoplasias , Fenótipo , Intervalo Livre de Progressão , Neoplasias Retais/genética , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
17.
Hum Genet ; 138(6): 661-672, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31069507

RESUMO

Tandem repeats (TRs) are widespread in the genomes of all living organisms. In eukaryotes, they are found in both coding and noncoding regions and have potential roles in the regulation of cellular processes such as transcription, translation and in the modification of protein structure. Recent studies have highlighted TRs as a key regulator of gene expression and a potential contributor to human evolution. Thus, TRs are emerging as an important source of variation that can result in differential gene expression at intra- and inter-species levels. In this study, we performed a genome-wide survey to identify TRs that have emerged in the human lineage. We further examined these loci to explore their potential functional significance for human evolution. We identified 152 human-specific TR (HSTR) loci containing a repeat unit of more than ten bases, with most of them showing a repeat count of two. Gene set enrichment analysis showed that HSTR-associated genes were associated with biological functions in brain development and synapse function. In addition, we compared gene expression of human HSTR loci with orthologues from non-human primates (NHP) in seven different tissues. Strikingly, the expression level of HSTR-associated genes in brain tissues was significantly higher in human than in NHP. These results suggest the possibility that de novo emergence of TRs could have resulted in altered gene expression in humans within a short-time frame and contributed to the rapid evolution of human brain function.


Assuntos
Encéfalo/metabolismo , Regulação da Expressão Gênica , Especificidade de Órgãos/genética , Sequências de Repetição em Tandem/genética , Animais , Sequência de Bases , Evolução Molecular , Genoma Humano/genética , Humanos , Taxa de Mutação , Primatas/genética , Homologia de Sequência do Ácido Nucleico
18.
Nat Commun ; 10(1): 2273, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118420

RESUMO

The human pathogen Helicobacter pylori displays extensive genetic diversity. While H. pylori is known to evolve during infection, population dynamics inside the gastric environment have not been extensively investigated. Here we obtained gastric biopsies from multiple stomach regions of 16 H. pylori-infected adults, and analyze the genomes of 10 H. pylori isolates from each biopsy. Phylogenetic analyses suggest location-specific evolution and bacterial migration between gastric regions. Migration is significantly more frequent between the corpus and the fundus than with the antrum, suggesting that physiological differences between antral and oxyntic mucosa contribute to spatial partitioning of H. pylori populations. Associations between H. pylori gene polymorphisms and stomach niches suggest that chemotaxis, regulatory functions and outer membrane proteins contribute to specific adaptation to the antral and oxyntic mucosa. Moreover, we show that antibiotics can induce severe population bottlenecks and likely play a role in shaping the population structure of H. pylori.


Assuntos
Adaptação Biológica/genética , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/genética , Taxa de Mutação , Adulto , Idoso , Biópsia , Quimiotaxia/genética , Mucosa Gástrica/patologia , Genoma Bacteriano/genética , Infecções por Helicobacter/patologia , Helicobacter pylori/isolamento & purificação , Helicobacter pylori/patogenicidade , Humanos , Pessoa de Meia-Idade , Filogenia , Polimorfismo Genético
19.
Horm Metab Res ; 51(4): 248-255, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31022740

RESUMO

The objective of the study is the functional characterization of a novel POU1F1 c.605delC mutation in combined pituitary hormone deficiency (CPHD) and to report the clinical and genetic details of 160 growth hormone deficiency patients. Screening of GH1, GHRHR, POU1F1, PROP1, and HESX1 genes by Sanger sequencing was carried out in 160 trios and 100 controls followed by characterization of the POU1F1 c.605delC mutation by expression studies including site directed mutagenesis, co-transfection, protein degradation, and luciferase assays to compare the wild type and mutant POU1F1. In vitro studies showed that the POU1F1 c.605delC mutation codes for a truncated protein with reduced transactivation capacity on its downstream effectors, viz., growth hormone (GH) and prolactin (PRL) causing severe CPHD. Experiments using different protease inhibitors reveal rescue of the protein upon blockage of the lysosomal pathway that might be useful in novel drug designing using targeted approach thereby maintaining the milieu and preventing/delaying the disease. The study provides an insight into the disease causing mechanism of POU1F1 c.605delC mutation identified in a CPHD child with severe short stature and failure to thrive. It also shows mutation effect on the expression, function and turnover of protein and highlights mechanistic details by which these potent regulators may operate.


Assuntos
Nanismo Hipofisário/genética , Testes Genéticos , Mutação/genética , Fator de Transcrição Pit-1/genética , Criança , Feminino , Hormônio do Crescimento Humano/genética , Humanos , Hipopituitarismo/genética , Masculino , Proteínas Mutantes/metabolismo , Taxa de Mutação , Prolactina/genética , Domínios Proteicos , Proteólise , Fator de Transcrição Pit-1/química , Ativação Transcricional/genética
20.
Med Sci (Paris) ; 35(3): 245-251, 2019 Mar.
Artigo em Francês | MEDLINE | ID: mdl-30931909

RESUMO

Alfred H. Sturtevant was the first to raise the question: why does the mutation rate not become reduced to zero? Indeed, most new mutations with a phenotypic effect are deleterious. Therefore, individuals who produce less mutants produce more viable and fertile offspring. Consequently, natural selection should increase the frequency of antimutator genotypes and progressively reduce the mutation rate to zero. However, no species has ever been found with a mutation rate equal to zero. Recent analyses suggest that setting the mutation rate above zero depends mainly on the effective size of the genome and the effective population size. The mutation rate is a trade-off between natural selection that operates to improve replication fidelity and the random genetic drift that sets the ultimate lower limit. This trade off illustrates the limitation of the power of natural selection in a world where natural populations have a finite size.


Assuntos
Evolução Molecular , Taxa de Mutação , Animais , Drosophila/genética , Genes Letais/fisiologia , Deriva Genética , Humanos , Relação entre Gerações , Modelos Genéticos , Mutação/fisiologia , Seleção Genética/genética
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