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1.
Nat Commun ; 12(1): 1434, 2021 03 04.
Artículo en Inglés | MEDLINE | ID: mdl-33664264

RESUMEN

Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour samples reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression.


Asunto(s)
Aneuploidia , Variaciones en el Número de Copia de ADN/genética , Genoma Humano/genética , Melanoma/genética , Neoplasias Cutáneas/genética , Progresión de la Enfermedad , Exoma/genética , Humanos , Mutación INDEL/genética , Melanocitos/patología , Mutación Puntual/genética , Polimorfismo de Nucleótido Simple/genética , Secuenciación del Exoma Completo , Secuenciación Completa del Genoma
2.
Nat Commun ; 12(1): 1485, 2021 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-33674578

RESUMEN

Yeast whole genome sequencing (WGS) lacks end-to-end workflows that identify genetic engineering. Here we present Prymetime, a tool that assembles yeast plasmids and chromosomes and annotates genetic engineering sequences. It is a hybrid workflow-it uses short and long reads as inputs to perform separate linear and circular assembly steps. This structure is necessary to accurately resolve genetic engineering sequences in plasmids and the genome. We show this by assembling diverse engineered yeasts, in some cases revealing unintended deletions and integrations. Furthermore, the resulting whole genomes are high quality, although the underlying assembly software does not consistently resolve highly repetitive genome features. Finally, we assemble plasmids and genome integrations from metagenomic sequencing, even with 1 engineered cell in 1000. This work is a blueprint for building WGS workflows and establishes WGS-based identification of yeast genetic engineering.


Asunto(s)
Ingeniería Genética/métodos , Genoma Fúngico , Saccharomyces cerevisiae/genética , Secuenciación Completa del Genoma/métodos , Secuencia de Bases , Cromosomas , Cromosomas Artificiales de Levadura , Clonación Molecular , Simulación por Computador , Mapeo Contig/métodos , Metagenoma , Metagenómica , Plásmidos , Programas Informáticos , Transformación Genética
3.
Euro Surveill ; 26(12)2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33769251

RESUMEN

The emergence of SARS-CoV-2 P.1 lineage coincided with a surge in hospitalisations in the North region of Brazil. In the South region's Rio Grande do Sul state, severe COVID-19 case numbers rose 3.8 fold in February 2021. During that month, at a COVID-19 referral hospital in this state, whole-genome sequencing of a subset of cases' specimens (n = 27) revealed P.1 lineage SARS-CoV-2 in most (n = 24). Findings raise concerns regarding a possible association between lineage P.1 and rapid case and hospitalisation increases.


Asunto(s)
/diagnóstico , /aislamiento & purificación , Brasil/epidemiología , Hospitalización/estadística & datos numéricos , Humanos , Secuenciación Completa del Genoma
4.
Sci Rep ; 11(1): 6009, 2021 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-33727674

RESUMEN

The South Korean government effectively contained the coronavirus disease-2019 (COVID-19) outbreak primarily associated with a religious group. We conducted SARS-CoV-2 whole genome sequencing of 66 cases to investigate connections among the initial South Korean cases and the religious group outbreak. We assessed the accuracy of genomic investigation by comparing the whole genome sequences with comprehensive contact tracing records. Five transmission clusters were estimated among the 15 initial cases. The six close-contact cases and two potential exposure pairs identified by contact tracing showed two or fewer nucleotide base differences. Additionally, we identified two transmission clusters that were phylogenetically distinct from the initial clusters, sharing common G11083T, G26144T, and C14805T markers. The strain closest to the two additional clusters was identified from a pair of identical sequences isolated from individuals who traveled from Wuhan to Italy. Our findings provide insights into the origins of community spread of COVID-19.


Asunto(s)
/patología , /genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , /transmisión , Niño , Preescolar , Trazado de Contacto , Brotes de Enfermedades , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Filogenia , ARN Viral/química , ARN Viral/genética , ARN Viral/metabolismo , República de Corea/epidemiología , /aislamiento & purificación , Secuenciación Completa del Genoma , Adulto Joven
5.
Nat Commun ; 12(1): 1504, 2021 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-33686085

RESUMEN

Elucidating functionality in non-coding regions is a key challenge in human genomics. It has been shown that intolerance to variation of coding and proximal non-coding sequence is a strong predictor of human disease relevance. Here, we integrate intolerance to variation, functional genomic annotations and primary genomic sequence to build JARVIS: a comprehensive deep learning model to prioritize non-coding regions, outperforming other human lineage-specific scores. Despite being agnostic to evolutionary conservation, JARVIS performs comparably or outperforms conservation-based scores in classifying pathogenic single-nucleotide and structural variants. In constructing JARVIS, we introduce the genome-wide residual variation intolerance score (gwRVIS), applying a sliding-window approach to whole genome sequencing data from 62,784 individuals. gwRVIS distinguishes Mendelian disease genes from more tolerant CCDS regions and highlights ultra-conserved non-coding elements as the most intolerant regions in the human genome. Both JARVIS and gwRVIS capture previously inaccessible human-lineage constraint information and will enhance our understanding of the non-coding genome.


Asunto(s)
Aprendizaje Profundo , Genoma Humano , Genómica , ADN Intergénico , Variación Genética , Humanos , Análisis de Secuencia de ADN , Secuenciación Completa del Genoma
6.
Science ; 371(6535): 1249-1253, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33737485

RESUMEN

Although cell lineage information is fundamental to understanding organismal development, very little direct information is available for humans. We performed high-depth (250×) whole-genome sequencing of multiple tissues from three individuals to identify hundreds of somatic single-nucleotide variants (sSNVs). Using these variants as "endogenous barcodes" in single cells, we reconstructed early embryonic cell divisions. Targeted sequencing of clonal sSNVs in different organs (about 25,000×) and in more than 1000 cortical single cells, as well as single-nucleus RNA sequencing and single-nucleus assay for transposase-accessible chromatin sequencing of ~100,000 cortical single cells, demonstrated asymmetric contributions of early progenitors to extraembryonic tissues, distinct germ layers, and organs. Our data suggest onset of gastrulation at an effective progenitor pool of about 170 cells and about 50 to 100 founders for the forebrain. Thus, mosaic mutations provide a permanent record of human embryonic development at very high resolution.


Asunto(s)
Linaje de la Célula , Gastrulación , Mutación , Células-Madre Neurales/citología , Prosencéfalo/citología , Adolescente , Adulto , División Celular , Células Clonales/citología , Desarrollo Embrionario/genética , Femenino , Gástrula/citología , Variación Genética , Estratos Germinativos/citología , Humanos , Masculino , Neuronas/citología , Organogénesis , Polimorfismo de Nucleótido Simple , Prosencéfalo/embriología , Análisis de la Célula Individual , Secuenciación Completa del Genoma
7.
BMC Plant Biol ; 21(1): 126, 2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33658004

RESUMEN

BACKGROUND: Melon is a very important horticultural crop produced worldwide with high phenotypic diversity. Fruit size is among the most important domestication and differentiation traits in melon. The molecular mechanisms of fruit size in melon are largely unknown. RESULTS: Two high-density genetic maps were constructed by whole-genome resequencing with two F2 segregating populations (WAP and MAP) derived from two crosses (cultivated agrestis × wild agrestis and cultivated melo × cultivated agrestis). We obtained 1,871,671 and 1,976,589 high quality SNPs that show differences between parents in WAP and MAP. A total of 5138 and 5839 recombination events generated 954 bins in WAP and 1027 bins in MAP with the average size of 321.3 Kb and 301.4 Kb respectively. All bins were mapped onto 12 linkage groups in WAP and MAP. The total lengths of two linkage maps were 904.4 cM (WAP) and 874.5 cM (MAP), covering 86.6% and 87.4% of the melon genome. Two loci for fruit size were identified on chromosome 11 in WAP and chromosome 5 in MAP, respectively. An auxin response factor and a YABBY transcription factor were inferred to be the candidate genes for both loci. CONCLUSION: The high-resolution genetic maps and QTLs analyses for fruit size described here will provide a better understanding the genetic basis of domestication and differentiation, and provide a valuable tool for map-based cloning and molecular marker assisted breeding.


Asunto(s)
Cucumis melo/genética , Frutas/genética , Genes de Plantas , Sitios de Carácter Cuantitativo , Mapeo Cromosómico , Cromosomas de las Plantas , Cucumis melo/crecimiento & desarrollo , Frutas/crecimiento & desarrollo , Genoma de Planta , Polimorfismo de Nucleótido Simple , Recombinación Genética , Secuenciación Completa del Genoma
8.
Yi Chuan ; 43(2): 108-117, 2021 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-33724214

RESUMEN

The advent and development of single-cell whole-genome sequencing (scWGS) technology has shed lights on the genomic heterogeneities within biosamples at the single-cell resolution. The technology is particularly well-established in the recent decade and witnesses a variety of clinical applications, such as circulating tumor cell (CTC) detection and preimplantation genetic diagnosis/screening (PGD/PGS). In this review, we summarize the latest practical breakthroughs of scWGS in the field of biomedicine, with the hope of providing a guideline to apply single-cell genomic sequencing in clinical researches.


Asunto(s)
Diagnóstico Preimplantación , Femenino , Genoma , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Embarazo , Análisis de la Célula Individual , Tecnología , Secuenciación Completa del Genoma
9.
Transl Psychiatry ; 11(1): 160, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33723208

RESUMEN

Psychiatric symptoms are seen in some COVID-19 patients, as direct or indirect sequelae, but it is unclear whether SARS-CoV-2 infection interacts with underlying neuronal or psychiatric susceptibilities. Such interactions might arise from COVID-19 immune responses, from infection of neurons themselves or may reflect social-psychological causes. To clarify this we sought the key gene expression pathways altered in COVID-19 also affected in bipolar disorder, post-traumatic stress disorder (PTSD) and schizophrenia, since this may identify pathways of interaction that could be treatment targets. We performed large scale comparisons of whole transcriptome data and immune factor transcript data in peripheral blood mononuclear cells (PBMC) from COVID-19 patients and patients with psychiatric disorders. We also analysed genome-wide association study (GWAS) data for symptomatic COVID-19 patients, comparing GWAS and whole-genome sequence data from patients with bipolar disorder, PTSD and schizophrenia patients. These studies revealed altered signalling and ontology pathways shared by COVID-19 patients and the three psychiatric disorders. Finally, co-expression and network analyses identified gene clusters common to the conditions. COVID-19 patients had peripheral blood immune system profiles that overlapped with those of patients with psychiatric conditions. From the pathways identified, PTSD profiles were the most highly correlated with COVID-19, perhaps consistent with stress-immune system interactions seen in PTSD. We also revealed common inflammatory pathways that may exacerbate psychiatric disorders, which may support the usage of anti-inflammatory medications in these patients. It also highlights the potential clinical application of multi-level dataset studies in difficult-to-treat psychiatric disorders in this COVID-19 pandemic.


Asunto(s)
Trastorno Bipolar/genética , Esquizofrenia/genética , Trastornos por Estrés Postraumático/genética , Trastorno Bipolar/inmunología , Comorbilidad , Perfilación de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes , Estudio de Asociación del Genoma Completo , Genómica , Humanos , Inmunidad/genética , Inflamación/genética , Trastornos Mentales/genética , Trastornos Mentales/inmunología , Esquizofrenia/inmunología , Transducción de Señal/genética , Trastornos por Estrés Postraumático/inmunología , Secuenciación Completa del Genoma
10.
Methods Mol Biol ; 2291: 87-97, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33704749

RESUMEN

Today, whole genome sequencing (WGS)-based typing is the gold standard approach to detect outbreaks of Shiga toxin-producing Escherichia coli (STEC) and to differentiate them from sporadic cases. Here, we describe an optimized protocol to efficiently determine the genome sequences of STEC using short read Illumina technology and provide information on helpful tools for the subsequent bioinformatic analysis.


Asunto(s)
Biología Computacional , Brotes de Enfermedades , Infecciones por Escherichia coli , Genoma Bacteriano , Escherichia coli Shiga-Toxigénica/genética , Secuenciación Completa del Genoma , Infecciones por Escherichia coli/epidemiología , Infecciones por Escherichia coli/genética , Humanos
11.
Methods Mol Biol ; 2291: 99-117, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33704750

RESUMEN

Escherichia coli is a species of bacteria that can be present in a wide variety of mammalian hosts and potentially soil environments. E. coli has an open genome and can show considerable diversity in gene content between isolates. It is a reasonable assumption that gene content reflects evolution of strains in particular host environments and therefore can be used to predict the host most likely to be the source of an isolate. An extrapolation of this argument is that strains may also have gene content that favors success in multiple hosts and so the possibility of successful transmission from one host to another, for example, from cattle to human, can also be predicted based on gene content. In this methods chapter, we consider the issue of Shiga toxin (Stx)-producing E. coli (STEC) strains that are present in ruminants as the main host reservoir and for which we know that a subset causes life-threatening infections in humans. We show how the genome sequences of E. coli isolated from both cattle and humans can be used to build a classifier to predict human and cattle host association and how this can be applied to score key STEC serotypes known to be associated with human infection. With the example dataset used, serogroups O157, O26, and O111 show the highest, and O103 and O145 the lowest, predictions for human association. The long-term ambition is to combine such machine learning predictions with phylogeny to predict the zoonotic threat of an isolate based on its whole genome sequence (WGS).


Asunto(s)
Infecciones por Escherichia coli/genética , Genoma Bacteriano , Aprendizaje Automático , Filogenia , Serogrupo , Escherichia coli Shiga-Toxigénica , Secuenciación Completa del Genoma , Animales , Bovinos , Humanos , Escherichia coli Shiga-Toxigénica/clasificación , Escherichia coli Shiga-Toxigénica/genética
12.
Mem Inst Oswaldo Cruz ; 116: e200517, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33729319

RESUMEN

Molecular-typing can help in unraveling epidemiological scenarios and improvement for disease control strategies. A literature review of Mycobacterium tuberculosis transmission in Brazil through genotyping on 56 studies published from 1996-2019 was performed. The clustering rate for mycobacterial interspersed repetitive units - variable tandem repeats (MIRU-VNTR) of 1,613 isolates were: 73%, 33% and 28% based on 12, 15 and 24-loci, respectively; while for RFLP-IS6110 were: 84% among prison population in Rio de Janeiro, 69% among multidrug-resistant isolates in Rio Grande do Sul, and 56.2% in general population in São Paulo. These findings could improve tuberculosis (TB) surveillance and set up a solid basis to build a database of Mycobacterium genomes.


Asunto(s)
Repeticiones de Minisatélite/genética , Mycobacterium tuberculosis/genética , Polimorfismo de Longitud del Fragmento de Restricción/genética , Técnicas de Tipificación Bacteriana , Brasil/epidemiología , Genotipo , Humanos , Epidemiología Molecular , Mycobacterium tuberculosis/aislamiento & purificación , Secuenciación Completa del Genoma
13.
Elife ; 102021 03 17.
Artículo en Inglés | MEDLINE | ID: mdl-33729154

RESUMEN

Understanding the effectiveness of infection control methods in reducing and preventing SARS-CoV-2 transmission in healthcare settings is of high importance. We sequenced SARS-CoV-2 genomes for patients and healthcare workers (HCWs) across multiple geographically distinct UK hospitals, obtaining 173 high-quality SARS-CoV-2 genomes. We integrated patient movement and staff location data into the analysis of viral genome data to understand spatial and temporal dynamics of SARS-CoV-2 transmission. We identified eight patient contact clusters (PCC) with significantly increased similarity in genomic variants compared to non-clustered samples. Incorporation of HCW location further increased the number of individuals within PCCs and identified additional links in SARS-CoV-2 transmission pathways. Patients within PCCs carried viruses more genetically identical to HCWs in the same ward location. SARS-CoV-2 genome sequencing integrated with patient and HCW movement data increases identification of outbreak clusters. This dynamic approach can support infection control management strategies within the healthcare setting.


Asunto(s)
/transmisión , Infección Hospitalaria/transmisión , /genética , Anciano , Trazado de Contacto , Infección Hospitalaria/virología , Femenino , Personal de Salud , Humanos , Transmisión de Enfermedad Infecciosa de Paciente a Profesional , Transmisión de Enfermedad Infecciosa de Profesional a Paciente , Masculino , Secuenciación Completa del Genoma
14.
PLoS One ; 16(3): e0248371, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33755704

RESUMEN

Since its emergence in China, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide including Pakistan. During the pandemic, whole genome sequencing has played an important role in understanding the evolution and genomic diversity of SARS-CoV-2. Although an unprecedented number of SARS-CoV-2 full genomes have been submitted in GISAID and NCBI, data from Pakistan is scarce. We report the sequencing, genomic characterization, and phylogenetic analysis of five SARS-CoV-2 strains isolated from patients in Pakistan. The oropharyngeal swabs of patients that were confirmed positive for SARS-CoV-2 through real-time RT-PCR at National Institute of Health, Pakistan, were selected for whole-genome sequencing. Sequencing was performed using NEBNext Ultra II Directional RNA Library Prep kit for Illumina (NEW ENGLAND BioLabs Inc., MA, US) and Illumina iSeq 100 instrument (Illumina, San Diego, US). Based on whole-genome analysis, three Pakistani SARS-CoV-2 strains clustered into the 20A (GH) clade along with the strains from Oman, Slovakia, United States, and Pakistani strain EPI_ISL_513925. The two 19B (S)-clade strains were closely related to viruses from India and Oman. Overall, twenty-nine amino acid mutations were detected in the current study genome sequences, including fifteen missense and four novel mutations. Notably, we have found a D614G (aspartic acid to glycine) mutation in spike protein of the sequences from the GH clade. The G614 variant carrying the characteristic D614G mutation has been shown to be more infectious that lead to its rapid spread worldwide. This report highlights the detection of GH and S clade strains and G614 variant from Pakistan warranting large-scale whole-genome sequencing of strains prevalent in different regions to understand virus evolution and to explore their genetic diversity.


Asunto(s)
Variación Genética , Glicoproteína de la Espiga del Coronavirus/genética , Anciano de 80 o más Años , /virología , Femenino , Eliminación de Gen , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Orofaringe/virología , Pakistán , Filogenia , ARN Viral/química , ARN Viral/aislamiento & purificación , ARN Viral/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , /aislamiento & purificación , Glicoproteína de la Espiga del Coronavirus/metabolismo , Secuenciación Completa del Genoma , Adulto Joven
15.
N Engl J Med ; 384(10): 924-935, 2021 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-33704937

RESUMEN

BACKGROUND: Genomic analysis is essential for risk stratification in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Whole-genome sequencing is a potential replacement for conventional cytogenetic and sequencing approaches, but its accuracy, feasibility, and clinical utility have not been demonstrated. METHODS: We used a streamlined whole-genome sequencing approach to obtain genomic profiles for 263 patients with myeloid cancers, including 235 patients who had undergone successful cytogenetic analysis. We adapted sample preparation, sequencing, and analysis to detect mutations for risk stratification using existing European Leukemia Network (ELN) guidelines and to minimize turnaround time. We analyzed the performance of whole-genome sequencing by comparing our results with findings from cytogenetic analysis and targeted sequencing. RESULTS: Whole-genome sequencing detected all 40 recurrent translocations and 91 copy-number alterations that had been identified by cytogenetic analysis. In addition, we identified new clinically reportable genomic events in 40 of 235 patients (17.0%). Prospective sequencing of samples obtained from 117 consecutive patients was performed in a median of 5 days and provided new genetic information in 29 patients (24.8%), which changed the risk category for 19 patients (16.2%). Standard AML risk groups, as defined by sequencing results instead of cytogenetic analysis, correlated with clinical outcomes. Whole-genome sequencing was also used to stratify patients who had inconclusive results by cytogenetic analysis into risk groups in which clinical outcomes were measurably different. CONCLUSIONS: In our study, we found that whole-genome sequencing provided rapid and accurate genomic profiling in patients with AML or MDS. Such sequencing also provided a greater diagnostic yield than conventional cytogenetic analysis and more efficient risk stratification on the basis of standard risk categories. (Funded by the Siteman Cancer Research Fund and others.).


Asunto(s)
Análisis Citogenético , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/genética , Secuenciación Completa del Genoma , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Análisis de Supervivencia , Secuenciación Completa del Genoma/métodos
16.
Nat Commun ; 12(1): 1523, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33750782

RESUMEN

Enterococcus faecalis is a commensal and nosocomial pathogen, which is also ubiquitous in animals and insects, representing a classical generalist microorganism. Here, we study E. faecalis isolates ranging from the pre-antibiotic era in 1936 up to 2018, covering a large set of host species including wild birds, mammals, healthy humans, and hospitalised patients. We sequence the bacterial genomes using short- and long-read techniques, and identify multiple extant hospital-associated lineages, with last common ancestors dating back as far as the 19th century. We find a population cohesively connected through homologous recombination, a metabolic flexibility despite a small genome size, and a stable large core genome. Our findings indicate that the apparent hospital adaptations found in hospital-associated E. faecalis lineages likely predate the "modern hospital" era, suggesting selection in another niche, and underlining the generalist nature of this nosocomial pathogen.


Asunto(s)
Infección Hospitalaria/microbiología , Enterococcus faecalis/genética , Enterococcus faecalis/metabolismo , Prednisolona/metabolismo , Prednisolona/farmacología , Animales , Antibacterianos , Aves , Farmacorresistencia Bacteriana/genética , Enterococcus faecalis/efectos de los fármacos , Enterococcus faecalis/aislamiento & purificación , Genes MDR/genética , Genoma Bacteriano , Infecciones por Bacterias Grampositivas/microbiología , Hospitales , Especificidad del Huésped , Humanos , Filogenia , Factores de Virulencia , Secuenciación Completa del Genoma
17.
Sci Rep ; 11(1): 6625, 2021 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-33758205

RESUMEN

Coronavirus disease 2019 (COVID-19) has emerged in December 2019 when the first case was reported in Wuhan, China and turned into a pandemic with 27 million (September 9th) cases. Currently, there are over 95,000 complete genome sequences of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing COVID-19, in public databases, accompanying a growing number of studies. Nevertheless, there is still much to learn about the viral population variation when the virus is evolving as it continues to spread. We have analyzed SARS-CoV-2 genomes to identify the most variant sites, as well as the stable, conserved ones in samples collected in the Netherlands until June 2020. We identified the most frequent mutations in different geographies. We also performed a phylogenetic study focused on the Netherlands to detect novel variants emerging in the late stages of the pandemic and forming local clusters. We investigated the S and N proteins on SARS-CoV-2 genomes in the Netherlands and found the most variant and stable sites to guide development of diagnostics assays and vaccines. We observed that while the SARS-CoV-2 genome has accumulated mutations, diverging from reference sequence, the variation landscape is dominated by four mutations globally, suggesting the current reference does not represent the virus samples circulating currently. In addition, we detected novel variants of SARS-CoV-2 almost unique to the Netherlands that form localized clusters and region-specific sub-populations indicating community spread. We explored SARS-CoV-2 variants in the Netherlands until June 2020 within a global context; our results provide insight into the viral population diversity for localized efforts in tracking the transmission of COVID-19, as well as sequenced-based approaches in diagnostics and therapeutics. We emphasize that little diversity is observed globally in recent samples despite the increased number of mutations relative to the established reference sequence. We suggest sequence-based analyses should opt for a consensus representation to adequately cover the genomic variation observed to speed up diagnostics and vaccine design.


Asunto(s)
/patología , /genética , /virología , Bases de Datos Genéticas , Evolución Molecular , Genoma Viral , Humanos , Mutación , Tasa de Mutación , Países Bajos , Filogenia , /aislamiento & purificación , Secuenciación Completa del Genoma
18.
Nat Commun ; 12(1): 1269, 2021 02 24.
Artículo en Inglés | MEDLINE | ID: mdl-33627664

RESUMEN

Telomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas (n = 760) and characterize its features using multi-omics profiling. ALT-positive tumors are molecularly distinct from other neuroblastoma subtypes and enriched in a population-based clinical sequencing study cohort for relapsed cases. They display reduced ATRX/DAXX complex abundance, due to either ATRX mutations (55%) or low protein expression. The heterochromatic histone mark H3K9me3 recognized by ATRX is enriched at the telomeres of ALT-positive tumors. Notably, we find a high frequency of telomeric repeat loci with a neuroblastoma ALT-specific hotspot on chr1q42.2 and loss of the adjacent chromosomal segment forming a neo-telomere. ALT-positive neuroblastomas proliferate slowly, which is reflected by a protracted clinical course of disease. Nevertheless, children with an ALT-positive neuroblastoma have dismal outcome.


Asunto(s)
Secuenciación Completa del Genoma/métodos , Western Blotting , Exones/genética , Citometría de Flujo , Humanos , Proteoma/metabolismo , Estudios Retrospectivos , Análisis de Secuencia de ARN/métodos , Telómero/genética , Telómero/metabolismo , Homeostasis del Telómero/genética , Proteína Nuclear Ligada al Cromosoma X/genética
19.
Nat Commun ; 12(1): 763, 2021 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-33536429

RESUMEN

Human and animal infections with bacteria of the genus Sarcina (family Clostridiaceae) are associated with gastric dilation and emphysematous gastritis. However, the potential roles of sarcinae as commensals or pathogens remain unclear. Here, we investigate a lethal disease of unknown etiology that affects sanctuary chimpanzees (Pan troglodytes verus) in Sierra Leone. The disease, which we have named "epizootic neurologic and gastroenteric syndrome" (ENGS), is characterized by neurologic and gastrointestinal signs and results in death of the animals, even after medical treatment. Using a case-control study design, we show that ENGS is strongly associated with Sarcina infection. The microorganism is distinct from Sarcina ventriculi and other known members of its genus, based on bacterial morphology and growth characteristics. Whole-genome sequencing confirms this distinction and reveals the presence of genetic features that may account for the unusual virulence of the bacterium. Therefore, we propose that this organism be considered the representative of a new species, named "Candidatus Sarcina troglodytae". Our results suggest that a heretofore unrecognized complex of related sarcinae likely exists, some of which may be highly virulent. However, the potential role of "Ca. S. troglodytae" in the etiology of ENGS, alone or in combination with other factors, remains a topic for future research.


Asunto(s)
Enfermedades del Simio Antropoideo/diagnóstico , Enfisema/diagnóstico , Gastritis/diagnóstico , Infecciones por Bacterias Grampositivas/diagnóstico , Sarcina/genética , Animales , Enfermedades del Simio Antropoideo/microbiología , ADN Bacteriano/análisis , ADN Bacteriano/genética , Enfisema/microbiología , Gastritis/microbiología , Infecciones por Bacterias Grampositivas/microbiología , Infecciones por Bacterias Grampositivas/veterinaria , Humanos , Pan troglodytes , Sarcina/clasificación , Sarcina/patogenicidad , Sierra Leona , Virulencia/genética , Secuenciación Completa del Genoma/métodos
20.
Nat Med ; 27(3): 440-446, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33531709

RESUMEN

The first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in South Africa was identified on 5 March 2020, and by 26 March the country was in full lockdown (Oxford stringency index of 90)1. Despite the early response, by November 2020, over 785,000 people in South Africa were infected, which accounted for approximately 50% of all known African infections2. In this study, we analyzed 1,365 near whole genomes and report the identification of 16 new lineages of SARS-CoV-2 isolated between 6 March and 26 August 2020. Most of these lineages have unique mutations that have not been identified elsewhere. We also show that three lineages (B.1.1.54, B.1.1.56 and C.1) spread widely in South Africa during the first wave, comprising ~42% of all infections in the country at the time. The newly identified C lineage of SARS-CoV-2, C.1, which has 16 nucleotide mutations as compared with the original Wuhan sequence, including one amino acid change on the spike protein, D614G (ref. 3), was the most geographically widespread lineage in South Africa by the end of August 2020. An early South African-specific lineage, B.1.106, which was identified in April 2020 (ref. 4), became extinct after nosocomial outbreaks were controlled in KwaZulu-Natal Province. Our findings show that genomic surveillance can be implemented on a large scale in Africa to identify new lineages and inform measures to control the spread of SARS-CoV-2. Such genomic surveillance presented in this study has been shown to be crucial in the identification of the 501Y.V2 variant in South Africa in December 2020 (ref. 5).


Asunto(s)
/epidemiología , /genética , Conjuntos de Datos como Asunto , Genoma Viral , Humanos , Tipificación Molecular , Mutación , Pandemias , Filogenia , Filogeografía , Reacción en Cadena en Tiempo Real de la Polimerasa , /aislamiento & purificación , Análisis de Secuencia de ARN , Sudáfrica/epidemiología , Secuenciación Completa del Genoma
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