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1.
bioRxiv ; 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38712152

RESUMO

Cancer progression is an evolutionary process driven by the selection of cells adapted to gain growth advantage. We present the first formal study on the adaptation of gene expression in subclonal evolution. We model evolutionary changes in gene expression as stochastic Ornstein-Uhlenbeck processes, jointly leveraging the evolutionary history of subclones and single-cell expression data. Applying our model to sublines derived from single cells of a mouse melanoma revealed that sublines with distinct phenotypes are underlined by different patterns of gene expression adaptation, indicating non-genetic mechanisms of cancer evolution. Interestingly, sublines previously observed to be resistant to anti-CTLA-4 treatment showed adaptive expression of genes related to invasion and non-canonical Wnt signaling, whereas sublines that responded to treatment showed adaptive expression of genes related to proliferation and canonical Wnt signaling. Our results suggest that clonal phenotypes emerge as the result of specific adaptivity patterns of gene expression.

2.
medRxiv ; 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38585974

RESUMO

Most current studies rely on short-read sequencing to detect somatic structural variation (SV) in cancer genomes. Long-read sequencing offers the advantage of better mappability and long-range phasing, which results in substantial improvements in germline SV detection. However, current long-read SV detection methods do not generalize well to the analysis of somatic SVs in tumor genomes with complex rearrangements, heterogeneity, and aneuploidy. Here, we present Severus: a method for the accurate detection of different types of somatic SVs using a phased breakpoint graph approach. To benchmark various short- and long-read SV detection methods, we sequenced five tumor/normal cell line pairs with Illumina, Nanopore, and PacBio sequencing platforms; on this benchmark Severus showed the highest F1 scores (harmonic mean of the precision and recall) as compared to long-read and short-read methods. We then applied Severus to three clinical cases of pediatric cancer, demonstrating concordance with known genetic findings as well as revealing clinically relevant cryptic rearrangements missed by standard genomic panels.

3.
bioRxiv ; 2023 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-37333132

RESUMO

Intratumoral heterogeneity (ITH) can promote cancer progression and treatment failure, but the complexity of the regulatory programs and contextual factors involved complicates its study. To understand the specific contribution of ITH to immune checkpoint blockade (ICB) response, we generated single cell-derived clonal sublines from an ICB-sensitive and genetically and phenotypically heterogeneous mouse melanoma model, M4. Genomic and single cell transcriptomic analyses uncovered the diversity of the sublines and evidenced their plasticity. Moreover, a wide range of tumor growth kinetics were observed in vivo , in part associated with mutational profiles and dependent on T cell-response. Further inquiry into melanoma differentiation states and tumor microenvironment (TME) subtypes of untreated tumors from the clonal sublines demonstrated correlations between highly inflamed and differentiated phenotypes with the response to anti-CTLA-4 treatment. Our results demonstrate that M4 sublines generate intratumoral heterogeneity at both levels of intrinsic differentiation status and extrinsic TME profiles, thereby impacting tumor evolution during therapeutic treatment. These clonal sublines proved to be a valuable resource to study the complex determinants of response to ICB, and specifically the role of melanoma plasticity in immune evasion mechanisms.

4.
Genome Res ; 33(7): 1089-1100, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37316351

RESUMO

Recent studies exploring the impact of methylation in tumor evolution suggest that although the methylation status of many of the CpG sites are preserved across distinct lineages, others are altered as the cancer progresses. Because changes in methylation status of a CpG site may be retained in mitosis, they could be used to infer the progression history of a tumor via single-cell lineage tree reconstruction. In this work, we introduce the first principled distance-based computational method, Sgootr, for inferring a tumor's single-cell methylation lineage tree and for jointly identifying lineage-informative CpG sites that harbor changes in methylation status that are retained along the lineage. We apply Sgootr on single-cell bisulfite-treated whole-genome sequencing data of multiregionally sampled tumor cells from nine metastatic colorectal cancer patients, as well as multiregionally sampled single-cell reduced-representation bisulfite sequencing data from a glioblastoma patient. We show that the tumor lineages constructed reveal a simple model underlying tumor progression and metastatic seeding. A comparison of Sgootr against alternative approaches shows that Sgootr can construct lineage trees with fewer migration events and with more in concordance with the sequential-progression model of tumor evolution, with a running time a fraction of that used in prior studies. Lineage-informative CpG sites identified by Sgootr are in inter-CpG island (CGI) regions, as opposed to intra-CGIs, which have been the main regions of interest in genomic methylation-related analyses.


Assuntos
Metilação de DNA , Neoplasias , Humanos , Metilação de DNA/genética , Sulfitos , Análise de Sequência de DNA/métodos , Genoma , Neoplasias/genética , Ilhas de CpG/genética
6.
Nat Comput Sci ; 2(9): 577-583, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38177468

RESUMO

We introduce HUNTRESS, a computational method for mutational intratumor heterogeneity inference from noisy genotype matrices derived from single-cell sequencing data, the running time of which is linear with the number of cells and quadratic with the number of mutations. We prove that, under reasonable conditions, HUNTRESS computes the true progression history of a tumor with high probability. On simulated and real tumor sequencing data, HUNTRESS is demonstrated to be faster than available alternatives with comparable or better accuracy. Additionally, the progression histories of tumors inferred by HUNTRESS on real single-cell sequencing datasets agree with the best known evolution scenarios for the associated tumors.


Assuntos
Neoplasias , Humanos , Neoplasias/genética , Análise de Sequência , Mutação
7.
J Comput Biol ; 28(9): 857-879, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34297621

RESUMO

Single-cell sequencing (SCS) data have great potential in reconstructing the evolutionary history of tumors. Rapid advances in SCS technology in the past decade were followed by the design of various computational methods for inferring trees of tumor evolution. Some of the earliest methods were based on the direct search in the space of trees with the goal of finding the maximum likelihood tree. However, it can be shown that instead of searching directly in the tree space, we can perform a search in the space of binary matrices and obtain maximum likelihood tree directly from the maximum likelihood matrix. The potential of the latter tree search strategy has recently been recognized by different research groups and several related methods were published in the past 2 years. Here we provide a review of the theoretical background of these methods and a detailed discussion, which are largely missing in the available publications, of the correlation between the two tree search strategies. We also discuss each of the existing methods based on the search in the space of binary matrices and summarize the best-known single-cell DNA sequencing data sets, which can be used in the future for assessing performance on real data of newly developed methods.


Assuntos
Biologia Computacional/métodos , Mutação , Neoplasias/genética , Neoplasias/patologia , Análise de Célula Única/métodos , Aprendizado Profundo , Humanos , Funções Verossimilhança , Filogenia , Análise de Sequência de DNA
8.
Cell ; 184(8): 2239-2254.e39, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33831375

RESUMO

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.


Assuntos
Heterogeneidade Genética , Neoplasias/genética , Variações do Número de Cópias de DNA , DNA de Neoplasias/química , DNA de Neoplasias/metabolismo , Bases de Dados Genéticas , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Neoplasias/patologia , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma
9.
iScience ; 23(11): 101655, 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33117968

RESUMO

Principled computational approaches for tumor phylogeny reconstruction via single-cell sequencing typically aim to build the most likely perfect phylogeny tree from the noisy genotype matrix - which represents genotype calls of single cells. This problem is NP-hard, and as a result, existing approaches aim to solve relatively small instances of it through combinatorial optimization techniques or Bayesian inference. As expected, even when the goal is to infer basic topological features of the tumor phylogeny, rather than reconstructing the topology entirely, these approaches could be prohibitively slow. In this paper, we introduce fast deep learning solutions to the problems of inferring whether the most likely tree has a linear (chain) or branching topology and whether a perfect phylogeny is feasible from a given genotype matrix. We also present a reinforcement learning approach for reconstructing the most likely tumor phylogeny. This preliminary work demonstrates that data-driven approaches can reconstruct key features of tumor evolution.

10.
Bioinformatics ; 36(Suppl_1): i169-i176, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32657358

RESUMO

MOTIVATION: Recent advances in single-cell sequencing (SCS) offer an unprecedented insight into tumor emergence and evolution. Principled approaches to tumor phylogeny reconstruction via SCS data are typically based on general computational methods for solving an integer linear program, or a constraint satisfaction program, which, although guaranteeing convergence to the most likely solution, are very slow. Others based on Monte Carlo Markov Chain or alternative heuristics not only offer no such guarantee, but also are not faster in practice. As a result, novel methods that can scale up to handle the size and noise characteristics of emerging SCS data are highly desirable to fully utilize this technology. RESULTS: We introduce PhISCS-BnB (phylogeny inference using SCS via branch and bound), a branch and bound algorithm to compute the most likely perfect phylogeny on an input genotype matrix extracted from an SCS dataset. PhISCS-BnB not only offers an optimality guarantee, but is also 10-100 times faster than the best available methods on simulated tumor SCS data. We also applied PhISCS-BnB on a recently published large melanoma dataset derived from the sublineages of a cell line involving 20 clones with 2367 mutations, which returned the optimal tumor phylogeny in <4 h. The resulting phylogeny agrees with and extends the published results by providing a more detailed picture on the clonal evolution of the tumor. AVAILABILITY AND IMPLEMENTATION: https://github.com/algo-cancer/PhISCS-BnB. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Algoritmos , Neoplasias , Humanos , Cadeias de Markov , Neoplasias/genética , Filogenia , Análise de Sequência , Software
11.
Bioinformatics ; 36(Suppl_1): i427-i435, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32657374

RESUMO

MOTIVATION: As multi-region, time-series and single-cell sequencing data become more widely available; it is becoming clear that certain tumors share evolutionary characteristics with others. In the last few years, several computational methods have been developed with the goal of inferring the subclonal composition and evolutionary history of tumors from tumor biopsy sequencing data. However, the phylogenetic trees that they report differ significantly between tumors (even those with similar characteristics). RESULTS: In this article, we present a novel combinatorial optimization method, CONETT, for detection of recurrent tumor evolution trajectories. Our method constructs a consensus tree of conserved evolutionary trajectories based on the information about temporal order of alteration events in a set of tumors. We apply our method to previously published datasets of 100 clear-cell renal cell carcinoma and 99 non-small-cell lung cancer patients and identify both conserved trajectories that were reported in the original studies, as well as new trajectories. AVAILABILITY AND IMPLEMENTATION: CONETT is implemented in C++ and available at https://github.com/ehodzic/CONETT. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Filogenia , Software
12.
Nature ; 578(7793): 122-128, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32025013

RESUMO

Cancer develops through a process of somatic evolution1,2. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes3. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)4, we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.


Assuntos
Evolução Molecular , Genoma Humano/genética , Neoplasias/genética , Reparo do DNA/genética , Dosagem de Genes , Genes Supressores de Tumor , Variação Genética , Humanos , Mutagênese Insercional/genética
13.
Genome Res ; 29(11): 1860-1877, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31628256

RESUMO

Available computational methods for tumor phylogeny inference via single-cell sequencing (SCS) data typically aim to identify the most likely perfect phylogeny tree satisfying the infinite sites assumption (ISA). However, the limitations of SCS technologies including frequent allele dropout and variable sequence coverage may prohibit a perfect phylogeny. In addition, ISA violations are commonly observed in tumor phylogenies due to the loss of heterozygosity, deletions, and convergent evolution. In order to address such limitations, we introduce the optimal subperfect phylogeny problem which asks to integrate SCS data with matching bulk sequencing data by minimizing a linear combination of potential false negatives (due to allele dropout or variance in sequence coverage), false positives (due to read errors) among mutation calls, and the number of mutations that violate ISA (real or because of incorrect copy number estimation). We then describe a combinatorial formulation to solve this problem which ensures that several lineage constraints imposed by the use of variant allele frequencies (VAFs, derived from bulk sequence data) are satisfied. We express our formulation both in the form of an integer linear program (ILP) and-as a first in tumor phylogeny reconstruction-a Boolean constraint satisfaction problem (CSP) and solve them by leveraging state-of-the-art ILP/CSP solvers. The resulting method, which we name PhISCS, is the first to integrate SCS and bulk sequencing data while accounting for ISA violating mutations. In contrast to the alternative methods, typically based on probabilistic approaches, PhISCS provides a guarantee of optimality in reported solutions. Using simulated and real data sets, we demonstrate that PhISCS is more general and accurate than all available approaches.


Assuntos
Biologia Computacional/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/genética , Filogenia , Análise de Célula Única/métodos , Humanos , Neoplasias/patologia
14.
Bioinformatics ; 35(14): i379-i388, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31510674

RESUMO

MOTIVATION: Despite the remarkable advances in sequencing and computational techniques, noise in the data and complexity of the underlying biological mechanisms render deconvolution of the phylogenetic relationships between cancer mutations difficult. Besides that, the majority of the existing datasets consist of bulk sequencing data of single tumor sample of an individual. Accurate inference of the phylogenetic order of mutations is particularly challenging in these cases and the existing methods are faced with several theoretical limitations. To overcome these limitations, new methods are required for integrating and harnessing the full potential of the existing data. RESULTS: We introduce a method called Hintra for intra-tumor heterogeneity detection. Hintra integrates sequencing data for a cohort of tumors and infers tumor phylogeny for each individual based on the evolutionary information shared between different tumors. Through an iterative process, Hintra learns the repeating evolutionary patterns and uses this information for resolving the phylogenetic ambiguities of individual tumors. The results of synthetic experiments show an improved performance compared to two state-of-the-art methods. The experimental results with a recent Breast Cancer dataset are consistent with the existing knowledge and provide potentially interesting findings. AVAILABILITY AND IMPLEMENTATION: The source code for Hintra is available at https://github.com/sahandk/HINTRA.


Assuntos
Neoplasias , Software , Humanos , Mutação , Filogenia , Análise de Sequência
15.
Algorithms Mol Biol ; 14: 17, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31372179

RESUMO

We introduce a new dissimilarity measure between a pair of "clonal trees", each representing the progression and mutational heterogeneity of a tumor sample, constructed by the use of single cell or bulk high throughput sequencing data. In a clonal tree, each vertex represents a specific tumor clone, and is labeled with one or more mutations in a way that each mutation is assigned to the oldest clone that harbors it. Given two clonal trees, our multi-labeled tree dissimilarity (MLTD) measure is defined as the minimum number of mutation/label deletions, (empty) leaf deletions, and vertex (clonal) expansions, applied in any order, to convert each of the two trees to the maximum common tree. We show that the MLTD measure can be computed efficiently in polynomial time and it captures the similarity between trees of different clonal granularity well.

16.
Nat Commun ; 10(1): 2750, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227714

RESUMO

Understanding the clonal architecture and evolutionary history of a tumour poses one of the key challenges to overcome treatment failure due to resistant cell populations. Previously, studies on subclonal tumour evolution have been primarily based on bulk sequencing and in some recent cases on single-cell sequencing data. Either data type alone has shortcomings with regard to this task, but methods integrating both data types have been lacking. Here, we present B-SCITE, the first computational approach that infers tumour phylogenies from combined single-cell and bulk sequencing data. Using a comprehensive set of simulated data, we show that B-SCITE systematically outperforms existing methods with respect to tree reconstruction accuracy and subclone identification. B-SCITE provides high-fidelity reconstructions even with a modest number of single cells and in cases where bulk allele frequencies are affected by copy number changes. On real tumour data, B-SCITE generated mutation histories show high concordance with expert generated trees.


Assuntos
Evolução Clonal/genética , Biologia Computacional/métodos , Análise Mutacional de DNA/métodos , Modelos Genéticos , Neoplasias/genética , Algoritmos , Conjuntos de Dados como Assunto , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação , Filogenia , Análise de Célula Única/métodos , Software
17.
Nat Commun ; 9(1): 828, 2018 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-29483503

RESUMO

High-throughput sequencing provides the means to determine the allelic decomposition for any gene of interest-the number of copies and the exact sequence content of each copy of a gene. Although many clinically and functionally important genes are highly polymorphic and have undergone structural alterations, no high-throughput sequencing data analysis tool has yet been designed to effectively solve the full allelic decomposition problem. Here we introduce a combinatorial optimization framework that successfully resolves this challenging problem, including for genes with structural alterations. We provide an associated computational tool Aldy that performs allelic decomposition of highly polymorphic, multi-copy genes through using whole or targeted genome sequencing data. For a large diverse sequencing data set, Aldy identifies multiple rare and novel alleles for several important pharmacogenes, significantly improving upon the accuracy and utility of current genotyping assays. As more data sets become available, we expect Aldy to become an essential component of genotyping toolkits.


Assuntos
Alelos , Citocromo P-450 CYP2D6/genética , Genoma Humano , Genótipo , Polimorfismo Genético , Software , Mapeamento Cromossômico , Citocromo P-450 CYP2D6/classificação , Citocromo P-450 CYP2D6/metabolismo , Variações do Número de Cópias de DNA , Técnicas de Genotipagem , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Isoenzimas/classificação , Isoenzimas/genética , Isoenzimas/metabolismo , Fenótipo , Análise de Sequência de DNA
18.
J Comput Biol ; 24(6): 515-523, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28056180

RESUMO

Inference of intra-tumor heterogeneity can provide valuable insight into cancer evolution. Somatic mutations detected by sequencing can help estimate the purity of a tumor sample and reconstruct its subclonal composition. Although several methods have been developed to infer intra-tumor heterogeneity, the majority of these tools rely on variant allele frequencies as estimated via ultra-deep sequencing from multiple samples of the same tumor. In practice, obtaining sequencing data from a large number of samples per patient is only feasible in a few cancer types such as liquid tumors, or in rare cases involving solid tumors selected for research. We introduce CTPsingle, which aims at inferring the subclonal composition by using low-coverage sequencing data from a single tumor sample. We show that CTPsingle is able to infer the purity and the clonality of single-sample tumors with high accuracy, even restricted to a coverage depth of ∼30 × .


Assuntos
Algoritmos , Evolução Clonal , Biologia Computacional/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/genética , Análise de Célula Única/métodos , Variações do Número de Cópias de DNA , Frequência do Gene , Humanos , Modelos Genéticos , Reconhecimento Automatizado de Padrão/métodos , Software
19.
Bioinformatics ; 31(12): i27-34, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-26072492

RESUMO

MOTIVATION: CYP2D6 is highly polymorphic gene which encodes the (CYP2D6) enzyme, involved in the metabolism of 20-25% of all clinically prescribed drugs and other xenobiotics in the human body. CYP2D6 genotyping is recommended prior to treatment decisions involving one or more of the numerous drugs sensitive to CYP2D6 allelic composition. In this context, high-throughput sequencing (HTS) technologies provide a promising time-efficient and cost-effective alternative to currently used genotyping techniques. To achieve accurate interpretation of HTS data, however, one needs to overcome several obstacles such as high sequence similarity and genetic recombinations between CYP2D6 and evolutionarily related pseudogenes CYP2D7 and CYP2D8, high copy number variation among individuals and short read lengths generated by HTS technologies. RESULTS: In this work, we present the first algorithm to computationally infer CYP2D6 genotype at basepair resolution from HTS data. Our algorithm is able to resolve complex genotypes, including alleles that are the products of duplication, deletion and fusion events involving CYP2D6 and its evolutionarily related cousin CYP2D7. Through extensive experiments using simulated and real datasets, we show that our algorithm accurately solves this important problem with potential clinical implications. AVAILABILITY AND IMPLEMENTATION: Cypiripi is available at http://sfu-compbio.github.io/cypiripi.


Assuntos
Citocromo P-450 CYP2D6/classificação , Citocromo P-450 CYP2D6/genética , Variações do Número de Cópias de DNA , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Polimorfismo Genético/genética , Software , Alelos , Genótipo , Humanos , Pseudogenes
20.
Bioinformatics ; 31(9): 1349-56, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25568283

RESUMO

MOTIVATION: Intra-tumor heterogeneity presents itself through the evolution of subclones during cancer progression. Although recent research suggests that this heterogeneity has clinical implications, in silico determination of the clonal subpopulations remains a challenge. RESULTS: We address this problem through a novel combinatorial method, named clonality inference in tumors using phylogeny (CITUP), that infers clonal populations and their frequencies while satisfying phylogenetic constraints and is able to exploit data from multiple samples. Using simulated datasets and deep sequencing data from two cancer studies, we show that CITUP predicts clonal frequencies and the underlying phylogeny with high accuracy. AVAILABILITY AND IMPLEMENTATION: CITUP is freely available at: http://sourceforge.net/projects/citup/. CONTACT: cenk@sfu.ca SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Algoritmos , Evolução Clonal , Neoplasias/genética , Filogenia , Análise Mutacional de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Mieloide Aguda/genética , Mutação
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