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1.
Cell ; 148(4): 780-91, 2012 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-22341448

RESUMO

The Tasmanian devil (Sarcophilus harrisii), the largest marsupial carnivore, is endangered due to a transmissible facial cancer spread by direct transfer of living cancer cells through biting. Here we describe the sequencing, assembly, and annotation of the Tasmanian devil genome and whole-genome sequences for two geographically distant subclones of the cancer. Genomic analysis suggests that the cancer first arose from a female Tasmanian devil and that the clone has subsequently genetically diverged during its spread across Tasmania. The devil cancer genome contains more than 17,000 somatic base substitution mutations and bears the imprint of a distinct mutational process. Genotyping of somatic mutations in 104 geographically and temporally distributed Tasmanian devil tumors reveals the pattern of evolution and spread of this parasitic clonal lineage, with evidence of a selective sweep in one geographical area and persistence of parallel lineages in other populations.


Assuntos
Neoplasias Faciais/veterinária , Instabilidade Genômica , Marsupiais/genética , Mutação , Animais , Evolução Clonal , Espécies em Perigo de Extinção , Neoplasias Faciais/epidemiologia , Neoplasias Faciais/genética , Neoplasias Faciais/patologia , Feminino , Estudo de Associação Genômica Ampla , Masculino , Dados de Sequência Molecular , Tasmânia/epidemiologia
2.
PLoS Pathog ; 17(8): e1009772, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34352039

RESUMO

Understanding SARS-CoV-2 evolution and host immunity is critical to control COVID-19 pandemics. At the core is an arms-race between SARS-CoV-2 antibody and angiotensin-converting enzyme 2 (ACE2) recognition, a function of the viral protein spike. Mutations in spike impacting antibody and/or ACE2 binding are appearing worldwide, imposing the need to monitor SARS-CoV2 evolution and dynamics in the population. Determining signatures in SARS-CoV-2 that render the virus resistant to neutralizing antibodies is critical. We engineered 25 spike-pseudotyped lentiviruses containing individual and combined mutations in the spike protein, including all defining mutations in the variants of concern, to identify the effect of single and synergic amino acid substitutions in promoting immune escape. We confirmed that E484K evades antibody neutralization elicited by infection or vaccination, a capacity augmented when complemented by K417N and N501Y mutations. In silico analysis provided an explanation for E484K immune evasion. E484 frequently engages in interactions with antibodies but not with ACE2. Importantly, we identified a novel amino acid of concern, S494, which shares a similar pattern. Using the already circulating mutation S494P, we found that it reduces antibody neutralization of convalescent and post-immunization sera, particularly when combined with E484K and with mutations able to increase binding to ACE2, such as N501Y. Our analysis of synergic mutations provides a signature for hotspots for immune evasion and for targets of therapies, vaccines and diagnostics.


Assuntos
Anticorpos Neutralizantes/imunologia , COVID-19/virologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Substituição de Aminoácidos/genética , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , Linhagem Celular , Humanos , Evasão da Resposta Imune , Mutação/genética , Ligação Proteica , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo
3.
Plant J ; 107(2): 613-628, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33960539

RESUMO

Traditional crops have historically provided accessible and affordable nutrition to millions of rural dwellers but have been neglected, with most modern agricultural systems over-reliant on a small number of internationally traded crops. Traditional crops are typically well-adapted to local agro-ecological conditions and many are nutrient-dense. They can play a vital role in local food systems through enhanced nutrition (particularly where diets are dominated by starch crops), food security and livelihoods for smallholder farmers, and a climate-resilient and biodiverse agriculture. Using short-read, long-read and phased sequencing technologies, we generated a high-quality chromosome-level genome assembly for Amaranthus cruentus, an under-researched crop with micronutrient- and protein-rich leaves and gluten-free seed, but lacking improved varieties, with respect to productivity and quality traits. The 370.9 Mb genome demonstrates a shared whole genome duplication with a related species, Amaranthus hypochondriacus. Comparative genome analysis indicates chromosomal loss and fusion events following genome duplication that are common to both species, as well as fission of chromosome 2 in A. cruentus alone, giving rise to a haploid chromosome number of 17 (versus 16 in A. hypochondriacus). Genomic features potentially underlying the nutritional value of this crop include two A. cruentus-specific genes with a likely role in phytic acid synthesis (an anti-nutrient), expansion of ion transporter gene families, and identification of biosynthetic gene clusters conserved within the amaranth lineage. The A. cruentus genome assembly will underpin much-needed research and global breeding efforts to develop improved varieties for economically viable cultivation and realization of the benefits to global nutrition security and agrobiodiversity.


Assuntos
Amaranthus/genética , Cromossomos de Plantas/genética , Produtos Agrícolas/genética , Evolução Molecular , Genoma de Planta/genética , Família Multigênica/genética , Valor Nutritivo/genética , Amaranthus/metabolismo , Mapeamento Cromossômico , Genes de Plantas/genética , Filogenia
4.
BMC Bioinformatics ; 22(1): 569, 2021 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-34837944

RESUMO

BACKGROUND: Efficient and effective genome scaffolding tools are still in high demand for generating reference-quality assemblies. While long read data itself is unlikely to create a chromosome-scale assembly for most eukaryotic species, the inexpensive Hi-C sequencing technology, capable of capturing the chromosomal profile of a genome, is now widely used to complete the task. However, the existing Hi-C based scaffolding tools either require a priori chromosome number as input, or lack the ability to build highly continuous scaffolds. RESULTS: We design and develop a novel Hi-C based scaffolding tool, pin_hic, which takes advantage of contact information from Hi-C reads to construct a scaffolding graph iteratively based on N-best neighbors of contigs. Subsequent to scaffolding, it identifies potential misjoins and breaks them to keep the scaffolding accuracy. Through our tests on three long read based de novo assemblies from three different species, we demonstrate that pin_hic is more efficient than current standard state-of-art tools, and it can generate much more continuous scaffolds, while achieving a higher or comparable accuracy. CONCLUSIONS: Pin_hic is an efficient Hi-C based scaffolding tool, which can be useful for building chromosome-scale assemblies. As many sequencing projects have been launched in the recent years, we believe pin_hic has potential to be applied in these projects and makes a meaningful contribution.


Assuntos
Genoma , Genômica , Cromossomos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Análise de Sequência de DNA
5.
Proc Natl Acad Sci U S A ; 114(5): 1081-1086, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-28096377

RESUMO

Phenotypic convergence between distantly related taxa often mirrors adaptation to similar selective pressures and may be driven by genetic convergence. The giant panda (Ailuropoda melanoleuca) and red panda (Ailurus fulgens) belong to different families in the order Carnivora, but both have evolved a specialized bamboo diet and adaptive pseudothumb, representing a classic model of convergent evolution. However, the genetic bases of these morphological and physiological convergences remain unknown. Through de novo sequencing the red panda genome and improving the giant panda genome assembly with added data, we identified genomic signatures of convergent evolution. Limb development genes DYNC2H1 and PCNT have undergone adaptive convergence and may be important candidate genes for pseudothumb development. As evolutionary responses to a bamboo diet, adaptive convergence has occurred in genes involved in the digestion and utilization of bamboo nutrients such as essential amino acids, fatty acids, and vitamins. Similarly, the umami taste receptor gene TAS1R1 has been pseudogenized in both pandas. These findings offer insights into genetic convergence mechanisms underlying phenotypic convergence and adaptation to a specialized bamboo diet.


Assuntos
Ailuridae/genética , Evolução Biológica , Genoma , Ursidae/genética , Adaptação Fisiológica , Ailuridae/classificação , Animais , Bambusa/química , Digestão/genética , Comportamento Alimentar , Herbivoria/genética , Mamíferos/classificação , Mamíferos/genética , Fenótipo , Filogenia , Pseudogenes , Receptores Acoplados a Proteínas G/genética , Alinhamento de Sequência , Homologia de Sequência do Ácido Nucleico , Especificidade da Espécie , Papilas Gustativas , Dedos do Pé/anatomia & histologia , Dedos do Pé/fisiologia , Ursidae/classificação
6.
Bioinformatics ; 34(17): 3022-3024, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29608694

RESUMO

Motivation: The recent technological advances in genome sequencing techniques have resulted in an exponential increase in the number of sequenced human and non-human genomes. The ever increasing number of assemblies generated by novel de novo pipelines and strategies demands the development of new software to evaluate assembly quality and completeness. One way to determine the completeness of an assembly is by detecting its Presence-Absence variations (PAV) with respect to a reference, where PAVs between two assemblies are defined as the sequences present in one assembly but entirely missing in the other one. Beyond assembly error or technology bias, PAVs can also reveal real genome polymorphism, consequence of species or individual evolution, or horizontal transfer from viruses and bacteria. Results: We present scanPAV, a pipeline for pairwise assembly comparison to identify and extract sequences present in one assembly but not the other. In this note, we use the GRCh38 reference assembly to assess the completeness of six human genome assemblies from various assembly strategies and sequencing technologies including Illumina short reads, 10× genomics linked-reads, PacBio and Oxford Nanopore long reads, and Bionano optical maps. We also discuss the PAV polymorphism of seven Tasmanian devil whole genome assemblies of normal animal tissues and devil facial tumour 1 (DFT1) and 2 (DFT2) samples, and the identification of bacterial sequences as contamination in some of the tumorous assemblies. Availability and implementation: The pipeline is available under the MIT License at https://github.com/wtsi-hpag/scanPAV. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Genoma , Animais , Mapeamento Cromossômico , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Análise de Sequência de DNA/métodos , Software
7.
Blood ; 128(1): e1-9, 2016 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-27121471

RESUMO

The diagnosis of hematologic malignancies relies on multidisciplinary workflows involving morphology, flow cytometry, cytogenetic, and molecular genetic analyses. Advances in cancer genomics have identified numerous recurrent mutations with clear prognostic and/or therapeutic significance to different cancers. In myeloid malignancies, there is a clinical imperative to test for such mutations in mainstream diagnosis; however, progress toward this has been slow and piecemeal. Here we describe Karyogene, an integrated targeted resequencing/analytical platform that detects nucleotide substitutions, insertions/deletions, chromosomal translocations, copy number abnormalities, and zygosity changes in a single assay. We validate the approach against 62 acute myeloid leukemia, 50 myelodysplastic syndrome, and 40 blood DNA samples from individuals without evidence of clonal blood disorders. We demonstrate robust detection of sequence changes in 49 genes, including difficult-to-detect mutations such as FLT3 internal-tandem and mixed-lineage leukemia (MLL) partial-tandem duplications, and clinically significant chromosomal rearrangements including MLL translocations to known and unknown partners, identifying the novel fusion gene MLL-DIAPH2 in the process. Additionally, we identify most significant chromosomal gains and losses, and several copy neutral loss-of-heterozygosity mutations at a genome-wide level, including previously unreported changes such as homozygosity for DNMT3A R882 mutations. Karyogene represents a dependable genomic diagnosis platform for translational research and for the clinical management of myeloid malignancies, which can be readily adapted for use in other cancers.


Assuntos
Genômica/métodos , Neoplasias Hematológicas , Leucemia Mieloide , Síndromes Mielodisplásicas , Proteínas de Transporte/genética , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Feminino , Forminas , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/genética , Masculino , Mutação , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Tirosina Quinase 3 Semelhante a fms/genética
9.
Am J Hum Genet ; 92(2): 301-6, 2013 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-23352258

RESUMO

A single Mendelian trait has been mapped to the human Y chromosome: Y-linked hearing impairment. The molecular basis of this disorder is unknown. Here, we report the detailed characterization of the DFNY1 Y chromosome and its comparison with a closely related Y chromosome from an unaffected branch of the family. The DFNY1 chromosome carries a complex rearrangement, including duplication of several noncontiguous segments of the Y chromosome and insertion of ∼160 kb of DNA from chromosome 1, in the pericentric region of Yp. This segment of chromosome 1 is derived entirely from within a known hearing impairment locus, DFNA49. We suggest that a third copy of one or more genes from the shared segment of chromosome 1 might be responsible for the hearing-loss phenotype.


Assuntos
Cromossomos Humanos Y/genética , Genes Ligados ao Cromossomo Y/genética , Perda Auditiva/genética , Feminino , Rearranjo Gênico/genética , Humanos , Masculino , Linhagem
10.
Nature ; 463(7278): 191-6, 2010 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-20016485

RESUMO

All cancers carry somatic mutations. A subset of these somatic alterations, termed driver mutations, confer selective growth advantage and are implicated in cancer development, whereas the remainder are passengers. Here we have sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person, providing the first comprehensive catalogue of somatic mutations from an individual cancer. The catalogue provides remarkable insights into the forces that have shaped this cancer genome. The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas the uneven distribution of mutations across the genome, with a lower prevalence in gene footprints, indicates that DNA repair has been preferentially deployed towards transcribed regions. The results illustrate the power of a cancer genome sequence to reveal traces of the DNA damage, repair, mutation and selection processes that were operative years before the cancer became symptomatic.


Assuntos
Genes Neoplásicos/genética , Genoma Humano/genética , Mutação/genética , Neoplasias/genética , Adulto , Linhagem Celular Tumoral , Dano ao DNA/genética , Análise Mutacional de DNA , Reparo do DNA/genética , Dosagem de Genes/genética , Humanos , Perda de Heterozigosidade/genética , Masculino , Melanoma/etiologia , Melanoma/genética , MicroRNAs/genética , Mutagênese Insercional/genética , Neoplasias/etiologia , Polimorfismo de Nucleotídeo Único/genética , Medicina de Precisão , Deleção de Sequência/genética , Raios Ultravioleta
11.
Nature ; 460(7253): 352-8, 2009 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-19606141

RESUMO

Schistosoma mansoni is responsible for the neglected tropical disease schistosomiasis that affects 210 million people in 76 countries. Here we present analysis of the 363 megabase nuclear genome of the blood fluke. It encodes at least 11,809 genes, with an unusual intron size distribution, and new families of micro-exon genes that undergo frequent alternative splicing. As the first sequenced flatworm, and a representative of the Lophotrochozoa, it offers insights into early events in the evolution of the animals, including the development of a body pattern with bilateral symmetry, and the development of tissues into organs. Our analysis has been informed by the need to find new drug targets. The deficits in lipid metabolism that make schistosomes dependent on the host are revealed, and the identification of membrane receptors, ion channels and more than 300 proteases provide new insights into the biology of the life cycle and new targets. Bioinformatics approaches have identified metabolic chokepoints, and a chemogenomic screen has pinpointed schistosome proteins for which existing drugs may be active. The information generated provides an invaluable resource for the research community to develop much needed new control tools for the treatment and eradication of this important and neglected disease.


Assuntos
Genoma Helmíntico/genética , Schistosoma mansoni/genética , Animais , Evolução Biológica , Éxons/genética , Genes de Helmintos/genética , Interações Hospedeiro-Parasita/genética , Íntrons/genética , Dados de Sequência Molecular , Mapeamento Físico do Cromossomo , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/embriologia , Schistosoma mansoni/fisiologia , Esquistossomose mansoni/tratamento farmacológico , Esquistossomose mansoni/parasitologia
12.
Genome Res ; 21(12): 2224-41, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21926179

RESUMO

Low-cost short read sequencing technology has revolutionized genomics, though it is only just becoming practical for the high-quality de novo assembly of a novel large genome. We describe the Assemblathon 1 competition, which aimed to comprehensively assess the state of the art in de novo assembly methods when applied to current sequencing technologies. In a collaborative effort, teams were asked to assemble a simulated Illumina HiSeq data set of an unknown, simulated diploid genome. A total of 41 assemblies from 17 different groups were received. Novel haplotype aware assessments of coverage, contiguity, structure, base calling, and copy number were made. We establish that within this benchmark: (1) It is possible to assemble the genome to a high level of coverage and accuracy, and that (2) large differences exist between the assemblies, suggesting room for further improvements in current methods. The simulated benchmark, including the correct answer, the assemblies, and the code that was used to evaluate the assemblies is now public and freely available from http://www.assemblathon.org/.


Assuntos
Genoma/fisiologia , Genômica/métodos , Análise de Sequência de DNA/métodos
13.
Artigo em Inglês | MEDLINE | ID: mdl-38905513

RESUMO

Long-range sequencing grants insight into additional genetic information beyond that which can be accessed by both short reads and modern long-read technology. Several new sequencing technologies are available for long-range datasets such as "Hi-C" and "Linked Reads" with high-throughput and high-resolution genome analysis, and are rapidly advancing the field of genome assembly, genome scaffolding, and more comprehensive variant identification. In this article, we focused on five major long-range sequencing technologies: high-throughput chromosome conformation capture (Hi-C), 10x Genomics Linked Reads, haplotagging, transposase enzyme linked long-read sequencing (TELL-seq), and single tube long fragment read (stLFR). We detailed the mechanisms and data products of the five platforms, introduced several of the most important applications, evaluated the quality of sequencing data from different platforms, and discussed the currently available bioinformatics tools. We hope this work will benefit the selection of appropriate long-range technology for specific biological studies.

14.
Cell Genom ; 4(2): 100484, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38232733

RESUMO

The epigenetic landscape of cancer is regulated by many factors, but primarily it derives from the underlying genome sequence. Chromothripsis is a catastrophic localized genome shattering event that drives, and often initiates, cancer evolution. We characterized five esophageal adenocarcinoma organoids with chromothripsis using long-read sequencing and transcriptome and epigenome profiling. Complex structural variation and subclonal variants meant that haplotype-aware de novo methods were required to generate contiguous cancer genome assemblies. Chromosomes were assembled separately and scaffolded using haplotype-resolved Hi-C reads, producing accurate assemblies even with up to 900 structural rearrangements. There were widespread differences between the chromothriptic and wild-type copies of chromosomes in topologically associated domains, chromatin accessibility, histone modifications, and gene expression. Differential epigenome peaks were most enriched within 10 kb of chromothriptic structural variants. Alterations in transcriptome and higher-order chromosome organization frequently occurred near differential epigenetic marks. Overall, chromothripsis reshapes gene regulation, causing coordinated changes in epigenetic landscape, transcription, and chromosome conformation.


Assuntos
Adenocarcinoma , Cromotripsia , Neoplasias Esofágicas , Humanos , Haplótipos , Cromatina , Genoma , Adenocarcinoma/genética
15.
Bioinformatics ; 28(4): 479-86, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22219203

RESUMO

MOTIVATION: RNA-seq is a powerful technology for the study of transcriptome profiles that uses deep-sequencing technologies. Moreover, it may be used for cellular phenotyping and help establishing the etiology of diseases characterized by abnormal splicing patterns. In RNA-Seq, the exact nature of splicing events is buried in the reads that span exon-exon boundaries. The accurate and efficient mapping of these reads to the reference genome is a major challenge. RESULTS: We developed PASSion, a pattern growth algorithm-based pipeline for splice site detection in paired-end RNA-Seq reads. Comparing the performance of PASSion to three existing RNA-Seq analysis pipelines, TopHat, MapSplice and HMMSplicer, revealed that PASSion is competitive with these packages. Moreover, the performance of PASSion is not affected by read length and coverage. It performs better than the other three approaches when detecting junctions in highly abundant transcripts. PASSion has the ability to detect junctions that do not have known splicing motifs, which cannot be found by the other tools. Of the two public RNA-Seq datasets, PASSion predicted ≈ 137,000 and 173,000 splicing events, of which on average 82 are known junctions annotated in the Ensembl transcript database and 18% are novel. In addition, our package can discover differential and shared splicing patterns among multiple samples. AVAILABILITY: The code and utilities can be freely downloaded from https://trac.nbic.nl/passion and ftp://ftp.sanger.ac.uk/pub/zn1/passion.


Assuntos
Algoritmos , Splicing de RNA , Análise de Sequência de RNA/métodos , Cromossomos Humanos Par 17 , Éxons , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , RNA/genética , Sítios de Splice de RNA , Software
16.
Twin Res Hum Genet ; 16(6): 1026-32, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24182360

RESUMO

It has been postulated that aging is the consequence of an accelerated accumulation of somatic DNA mutations and that subsequent errors in the primary structure of proteins ultimately reach levels sufficient to affect organismal functions. The technical limitations of detecting somatic changes and the lack of insight about the minimum level of erroneous proteins to cause an error catastrophe hampered any firm conclusions on these theories. In this study, we sequenced the whole genome of DNA in whole blood of two pairs of monozygotic (MZ) twins, 40 and 100 years old, by two independent next-generation sequencing (NGS) platforms (Illumina and Complete Genomics). Potentially discordant single-base substitutions supported by both platforms were validated extensively by Sanger, Roche 454, and Ion Torrent sequencing. We demonstrate that the genomes of the two twin pairs are germ-line identical between co-twins, and that the genomes of the 100-year-old MZ twins are discerned by eight confirmed somatic single-base substitutions, five of which are within introns. Putative somatic variation between the 40-year-old twins was not confirmed in the validation phase. We conclude from this systematic effort that by using two independent NGS platforms, somatic single nucleotide substitutions can be detected, and that a century of life did not result in a large number of detectable somatic mutations in blood. The low number of somatic variants observed by using two NGS platforms might provide a framework for detecting disease-related somatic variants in phenotypically discordant MZ twins.


Assuntos
Envelhecimento/genética , Células Sanguíneas/fisiologia , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Mutação/genética , Gêmeos Monozigóticos/genética , Adulto , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
Nucleic Acids Res ; 39(22): e148, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21948799

RESUMO

The development of technologies that allow the stable delivery of large genomic DNA fragments in mammalian systems is important for genetic studies as well as for applications in gene therapy. DNA transposons have emerged as flexible and efficient molecular vehicles to mediate stable cargo transfer. However, the ability to carry DNA fragments >10 kb is limited in most DNA transposons. Here, we show that the DNA transposon piggyBac can mobilize 100-kb DNA fragments in mouse embryonic stem (ES) cells, making it the only known transposon with such a large cargo capacity. The integrity of the cargo is maintained during transposition, the copy number can be controlled and the inserted giant transposons express the genomic cargo. Furthermore, these 100-kb transposons can also be excised from the genome without leaving a footprint. The development of piggyBac as a large cargo vector will facilitate a wider range of genetic and genomic applications.


Assuntos
Elementos de DNA Transponíveis , Vetores Genéticos , Genoma , Animais , Células Cultivadas , Células-Tronco Embrionárias/metabolismo , Loci Gênicos , Humanos , Hidrolases/genética , Camundongos
18.
Science ; 380(6642): 283-293, 2023 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-37079675

RESUMO

Tasmanian devils have spawned two transmissible cancer lineages, named devil facial tumor 1 (DFT1) and devil facial tumor 2 (DFT2). We investigated the genetic diversity and evolution of these clones by analyzing 78 DFT1 and 41 DFT2 genomes relative to a newly assembled, chromosome-level reference. Time-resolved phylogenetic trees reveal that DFT1 first emerged in 1986 (1982 to 1989) and DFT2 in 2011 (2009 to 2012). Subclone analysis documents transmission of heterogeneous cell populations. DFT2 has faster mutation rates than DFT1 across all variant classes, including substitutions, indels, rearrangements, transposable element insertions, and copy number alterations, and we identify a hypermutated DFT1 lineage with defective DNA mismatch repair. Several loci show plausible evidence of positive selection in DFT1 or DFT2, including loss of chromosome Y and inactivation of MGA, but none are common to both cancers. This study reveals the parallel long-term evolution of two transmissible cancers inhabiting a common niche in Tasmanian devils.


Assuntos
Evolução Molecular , Neoplasias Faciais , Marsupiais , Seleção Genética , Animais , Neoplasias Faciais/classificação , Neoplasias Faciais/genética , Neoplasias Faciais/veterinária , Genoma , Marsupiais/genética , Filogenia
19.
Nat Commun ; 14(1): 3412, 2023 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-37296119

RESUMO

Numerous novel adaptations characterise the radiation of notothenioids, the dominant fish group in the freezing seas of the Southern Ocean. To improve understanding of the evolution of this iconic fish group, here we generate and analyse new genome assemblies for 24 species covering all major subgroups of the radiation, including five long-read assemblies. We present a new estimate for the onset of the radiation at 10.7 million years ago, based on a time-calibrated phylogeny derived from genome-wide sequence data. We identify a two-fold variation in genome size, driven by expansion of multiple transposable element families, and use the long-read data to reconstruct two evolutionarily important, highly repetitive gene family loci. First, we present the most complete reconstruction to date of the antifreeze glycoprotein gene family, whose emergence enabled survival in sub-zero temperatures, showing the expansion of the antifreeze gene locus from the ancestral to the derived state. Second, we trace the loss of haemoglobin genes in icefishes, the only vertebrates lacking functional haemoglobins, through complete reconstruction of the two haemoglobin gene clusters across notothenioid families. Both the haemoglobin and antifreeze genomic loci are characterised by multiple transposon expansions that may have driven the evolutionary history of these genes.


Assuntos
Peixes , Perciformes , Animais , Peixes/genética , Genômica , Vertebrados , Filogenia , Hemoglobinas/genética , Regiões Antárticas
20.
Nat Cancer ; 4(11): 1575-1591, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37783803

RESUMO

Transmissible cancers are malignant cell lineages that spread clonally between individuals. Several such cancers, termed bivalve transmissible neoplasia (BTN), induce leukemia-like disease in marine bivalves. This is the case of BTN lineages affecting the common cockle, Cerastoderma edule, which inhabits the Atlantic coasts of Europe and northwest Africa. To investigate the evolution of cockle BTN, we collected 6,854 cockles, diagnosed 390 BTN tumors, generated a reference genome and assessed genomic variation across 61 tumors. Our analyses confirmed the existence of two BTN lineages with hemocytic origins. Mitochondrial variation revealed mitochondrial capture and host co-infection events. Mutational analyses identified lineage-specific signatures, one of which likely reflects DNA alkylation. Cytogenetic and copy number analyses uncovered pervasive genomic instability, with whole-genome duplication, oncogene amplification and alkylation-repair suppression as likely drivers. Satellite DNA distributions suggested ancient clonal origins. Our study illuminates long-term cancer evolution under the sea and reveals tolerance of extreme instability in neoplastic genomes.


Assuntos
Bivalves , Cardiidae , Leucemia , Neoplasias , Animais , Humanos , Cardiidae/genética , Evolução Clonal
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