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1.
Nat Commun ; 11(1): 4965, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009371

RESUMO

Next-generation sequencing (NGS) can identify novel cancer targets. However, interpreting the molecular findings and accessing drugs/clinical trials is challenging. Furthermore, many tumors show resistance to monotherapies. To implement a precision strategy, we initiated a multidisciplinary (basic/translational/clinical investigators, bioinformaticians, geneticists, and physicians from multiple specialties) molecular tumor board (MTB), which included a project manager to facilitate obtaining clinical-grade biomarkers (blood/tissue NGS, specific immunohistochemistry/RNA expression including for immune-biomarkers, per physician discretion) and medication-acquisition specialists/clinical trial coordinators/navigators to assist with medication access. The MTB comprehensively reviewed patient characteristics to develop N-of-One treatments implemented by the treating physician's direction under the auspices of a master protocol. Overall, 265/429 therapy-evaluable patients (62%) were matched to ≥1 recommended drug. Eighty-six patients (20%) matched to all drugs recommended by MTB, including combinatorial approaches, while 38% received physician's choice regimen, generally with unmatched approach/low degree of matching. Our results show that patients who receive MTB-recommended regimens (versus physician choice) have significantly longer progression-free (PFS) and overall survival (OS), and are better matched to therapy. High (≥50%) versus low (<50%) Matching Score therapy (roughly reflecting therapy matched to ≥50% versus <50% of alterations) independently correlates with longer PFS (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.50-0.80; P < 0.001) and OS (HR, 0.67; 95% CI, 0.50-0.90; P = 0.007) and higher stable disease ≥6 months/partial/complete remission rate (52.1% versus 30.4% P < 0.001) (all multivariate). In conclusion, patients who receive MTB-based therapy are better matched to their genomic alterations, and the degree of matching is an independent predictor of improved oncologic outcomes including survival.


Assuntos
Neoplasias/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , DNA Tumoral Circulante/genética , Intervalo Livre de Doença , Feminino , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Medicina de Precisão , Resultado do Tratamento , Adulto Jovem
2.
Mol Genet Genomics ; 295(6): 1537-1546, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32888056

RESUMO

Understanding how SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) efficiently reproduces itself by taking resources from the human host could facilitate the development of drugs against the virus. SARS-CoV-2 translates its own proteins by using the host tRNAs, so that its GC or codon usage should fit that of the host cells. It is necessary to study both the virus and human genomes in the light of evolution and adaptation. The SARS-CoV-2 virus has significantly lower GC content and GC3 as compared to human. However, when we selected a set of human genes that have similar GC properties to SARS-CoV-2, we found that these genes were enriched in particular pathways. Moreover, these human genes have the codon composition perfectly correlated with the SARS-CoV-2, and were extraordinarily highly expressed in human lung tissues, demonstrating that the SARS-CoV-2 genes have similar GC usage as compared to the lung expressed human genes. RSCU (relative synonymous codon usage) and CAI (codon adaptation index) profiles further support the matching between SARS-CoV-2 and lungs. Our study indicates that SARS-CoV-2 might have adapted to the human lung environment by observing the high correlation between GC usage of SARS-CoV-2 and human lung genes, which suggests the GC content of SARS-CoV-2 is optimized to take advantage of human lung tissues.


Assuntos
Betacoronavirus/genética , Uso do Códon , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Pulmão/virologia , Pneumonia Viral/genética , Pneumonia Viral/virologia , Composição de Bases , Genoma Humano , Genoma Viral , Interações Hospedeiro-Patógeno/genética , Humanos , Pandemias , RNA-Seq
3.
Nat Commun ; 11(1): 4703, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943643

RESUMO

Deep learning models have shown great promise in predicting regulatory effects from DNA sequence, but their informativeness for human complex diseases is not fully understood. Here, we evaluate genome-wide SNP annotations from two previous deep learning models, DeepSEA and Basenji, by applying stratified LD score regression to 41 diseases and traits (average N = 320K), conditioning on a broad set of coding, conserved and regulatory annotations. We aggregated annotations across all (respectively blood or brain) tissues/cell-types in meta-analyses across all (respectively 11 blood or 8 brain) traits. The annotations were highly enriched for disease heritability, but produced only limited conditionally significant results: non-tissue-specific and brain-specific Basenji-H3K4me3 for all traits and brain traits respectively. We conclude that deep learning models have yet to achieve their full potential to provide considerable unique information for complex disease, and that their conditional informativeness for disease cannot be inferred from their accuracy in predicting regulatory annotations.


Assuntos
Aprendizado Profundo , Doença/genética , Anotação de Sequência Molecular , Alelos , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Histonas/genética , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único
4.
Nat Commun ; 11(1): 4719, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948767

RESUMO

A small number of de novo assembled human genomes have been reported to date, and few have been complemented with population-based genetic variation, which is particularly important for North Africa, a region underrepresented in current genome-wide references. Here, we combine long- and short-read whole-genome sequencing data with recent assembly approaches into a de novo assembly of an Egyptian genome. The assembly demonstrates well-balanced quality metrics and is complemented with variant phasing via linked reads into haploblocks, which we associate with gene expression changes in blood. To construct an Egyptian genome reference, we identify genome-wide genetic variation within a cohort of 110 Egyptian individuals. We show that differences in allele frequencies and linkage disequilibrium between Egyptians and Europeans may compromise the transferability of European ancestry-based genetic disease risk and polygenic scores, substantiating the need for multi-ethnic genome references. Thus, the Egyptian genome reference will be a valuable resource for precision medicine.


Assuntos
Grupos Étnicos/genética , Genética Populacional , Genômica , Egito , Frequência do Gene , Variação Genética , Genoma Humano , Humanos , Desequilíbrio de Ligação , Masculino , Medicina de Precisão , Sequenciamento Completo do Genoma
5.
BMC Bioinformatics ; 21(1): 397, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32907531

RESUMO

BACKGROUND: Ion Torrent is one of the major next generation sequencing (NGS) technologies and it is frequently used in medical research and diagnosis. The built-in software for the Ion Torrent sequencing machines delivers the sequencing results in the BAM format. In addition to the usual SAM/BAM fields, the Ion Torrent BAM file includes technology-specific flow signal data. The flow signals occupy a big portion of the BAM file (about 75% for the human genome). Compressing SAM/BAM into CRAM format significantly reduces the space needed to store the NGS results. However, the tools for generating the CRAM formats are not designed to handle the flow signals. This missing feature has motivated us to develop a new program to improve the compression of the Ion Torrent files for long term archiving. RESULTS: In this paper, we present IonCRAM, the first reference-based compression tool to compress Ion Torrent BAM files for long term archiving. For the BAM files, IonCRAM could achieve a space saving of about 43%. This space saving is superior to what achieved with the CRAM format by about 8-9%. CONCLUSIONS: Reducing the space consumption of NGS data reduces the cost of storage and data transfer. Therefore, developing efficient compression software for clinical NGS data goes beyond the computational interest; as it ultimately contributes to the overall cost reduction of the clinical test. The space saving achieved by our tool is a practical step in this direction. The tool is open source and available at Code Ocean, github, and http://ioncram.saudigenomeproject.com .


Assuntos
Interface Usuário-Computador , Algoritmos , Bases de Dados Genéticas , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos
6.
PLoS One ; 15(8): e0232994, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866155

RESUMO

Transposable elements (TEs) are mobile genetic elements in eukaryotic genomes. Recent research highlights the important role of TEs in the embryogenesis, neurodevelopment, and immune functions. However, there is a lack of a one-stop and easy to use computational pipeline for expression analysis of both genes and locus-specific TEs from RNA-Seq data. Here, we present GeneTEFlow, a fully automated, reproducible and platform-independent workflow, for the comprehensive analysis of gene and locus-specific TEs expression from RNA-Seq data employing Nextflow and Docker technologies. This application will help researchers more easily perform integrated analysis of both gene and TEs expression, leading to a better understanding of roles of gene and TEs regulation in human diseases. GeneTEFlow is freely available at https://github.com/zhongw2/GeneTEFlow.


Assuntos
Elementos de DNA Transponíveis , RNA-Seq/estatística & dados numéricos , Software , Biologia Computacional , Bases de Dados de Ácidos Nucleicos/estatística & dados numéricos , Perfilação da Expressão Gênica/estatística & dados numéricos , Genoma Humano , Humanos , Fluxo de Trabalho
7.
Nat Commun ; 11(1): 4374, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873787

RESUMO

Oncogene amplification, a major driver of cancer pathogenicity, is often mediated through focal amplification of genomic segments. Recent results implicate extrachromosomal DNA (ecDNA) as the primary driver of focal copy number amplification (fCNA) - enabling gene amplification, rapid tumor evolution, and the rewiring of regulatory circuitry. Resolving an fCNA's structure is a first step in deciphering the mechanisms of its genesis and the fCNA's subsequent biological consequences. We introduce a computational method, AmpliconReconstructor (AR), for integrating optical mapping (OM) of long DNA fragments (>150 kb) with next-generation sequencing (NGS) to resolve fCNAs at single-nucleotide resolution. AR uses an NGS-derived breakpoint graph alongside OM scaffolds to produce high-fidelity reconstructions. After validating its performance through multiple simulation strategies, AR reconstructed fCNAs in seven cancer cell lines to reveal the complex architecture of ecDNA, a breakage-fusion-bridge and other complex rearrangements. By reconstructing the rearrangement signatures associated with an fCNA's generative mechanism, AR enables a more thorough understanding of the origins of fCNAs.


Assuntos
Amplificação de Genes , Genômica/métodos , Neoplasias/genética , Oncogenes/genética , Linhagem Celular Tumoral , Mapeamento Cromossômico/métodos , Análise Citogenética , Genoma Humano/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos
8.
Commun Biol ; 3(1): 538, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994472

RESUMO

The advent of portable nanopore sequencing devices has enabled DNA and RNA sequencing to be performed in the field or the clinic. However, advances in in situ genomics require parallel development of portable, offline solutions for the computational analysis of sequencing data. Here we introduce Genopo, a mobile toolkit for nanopore sequencing analysis. Genopo compacts popular bioinformatics tools to an Android application, enabling fully portable computation. To demonstrate its utility for in situ genome analysis, we use Genopo to determine the complete genome sequence of the human coronavirus SARS-CoV-2 in nine patient isolates sequenced on a nanopore device, with Genopo executing this workflow in less than 30 min per sample on a range of popular smartphones. We further show how Genopo can be used to profile DNA methylation in a human genome sample, illustrating a flexible, efficient architecture that is suitable to run many popular bioinformatics tools and accommodate small or large genomes. As the first ever smartphone application for nanopore sequencing analysis, Genopo enables the genomics community to harness this cheap, ubiquitous computational resource.


Assuntos
Betacoronavirus/genética , Biologia Computacional/métodos , Genoma Humano , Genoma Viral , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento Completo do Genoma/métodos , Betacoronavirus/patogenicidade , Telefone Celular/instrumentação , Biologia Computacional/instrumentação , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Metilação de DNA , Sequenciamento de Nucleotídeos em Larga Escala/instrumentação , Humanos , Nanoporos , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Sequenciamento Completo do Genoma/instrumentação
9.
Am J Hum Genet ; 107(3): 379-380, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32888506

RESUMO

It is imperative for participation in genetics and genomics research to reflect humanity's diversity so that all people can enjoy its benefits. This will take a concerted effort by the research community and must include greater engagement with individuals and communities underrepresented in research. In engaging with vulnerable populations, it is essential that researchers guard against harm resulting from their participation.


Assuntos
Pesquisa Biomédica , Variação Genética/genética , Populações Vulneráveis , Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Genoma Humano , Genômica , Genética Humana , Humanos
10.
Nat Commun ; 11(1): 4661, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938925

RESUMO

The recent years have seen a growing number of studies investigating evolutionary questions using ancient DNA. To address these questions, one of the most frequently-used method is principal component analysis (PCA). When PCA is applied to temporal samples, the sample dates are, however, ignored during analysis, leading to imperfect representations of samples in PC plots. Here, we present a factor analysis (FA) method in which individual scores are corrected for the effect of allele frequency drift over time. We obtained exact solutions for the estimates of corrected factors, and we provided a fast algorithm for their computation. Using computer simulations and ancient European samples, we compared geometric representations obtained from FA with PCA and with ancestry estimation programs. In admixture analyses, FA estimates agreed with tree-based statistics, and they were more accurate than those obtained from PCA projections and from ancestry estimation programs. A great advantage of FA over existing approaches is to improve descriptive analyses of ancient DNA samples without requiring inclusion of outgroup or present-day samples.


Assuntos
DNA Antigo/análise , Análise Fatorial , Genoma Humano , Metagenômica/estatística & dados numéricos , Algoritmos , Inglaterra , Europa (Continente) , Frequência do Gene , Deriva Genética , Genética Populacional/estatística & dados numéricos , Humanos , Modelos Genéticos , Análise de Componente Principal
11.
Nat Commun ; 11(1): 4826, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958757

RESUMO

DNA replication initiates from multiple genomic locations called replication origins. In metazoa, DNA sequence elements involved in origin specification remain elusive. Here, we examine pluripotent, primary, differentiating, and immortalized human cells, and demonstrate that a class of origins, termed core origins, is shared by different cell types and host ~80% of all DNA replication initiation events in any cell population. We detect a shared G-rich DNA sequence signature that coincides with most core origins in both human and mouse genomes. Transcription and G-rich elements can independently associate with replication origin activity. Computational algorithms show that core origins can be predicted, based solely on DNA sequence patterns but not on consensus motifs. Our results demonstrate that, despite an attributed stochasticity, core origins are chosen from a limited pool of genomic regions. Immortalization through oncogenic gene expression, but not normal cellular differentiation, results in increased stochastic firing from heterochromatin and decreased origin density at TAD borders.


Assuntos
DNA/biossíntese , DNA/química , Origem de Replicação/genética , Animais , Composição de Bases , Sequência de Bases , Carcinogênese , Diferenciação Celular , Células Cultivadas , Replicação do DNA/genética , Genoma Humano/genética , Heterocromatina/genética , Humanos , Camundongos , Motivos de Nucleotídeos , Transcrição Genética
12.
Nat Commun ; 11(1): 4748, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958763

RESUMO

The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.


Assuntos
Genoma Humano/genética , Mutação , Neoplasias/genética , Composição de Bases , DNA Intergênico , Bases de Dados Genéticas , Exoma/genética , Éxons , Humanos , Estudos Retrospectivos , Sequenciamento Completo do Exoma , Sequenciamento Completo do Genoma
13.
Nat Commun ; 11(1): 4794, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963235

RESUMO

Most human genomes are characterized by aligning individual reads to the reference genome, but accurate long reads and linked reads now enable us to construct accurate, phased de novo assemblies. We focus on a medically important, highly variable, 5 million base-pair (bp) region where diploid assembly is particularly useful - the Major Histocompatibility Complex (MHC). Here, we develop a human genome benchmark derived from a diploid assembly for the openly-consented Genome in a Bottle sample HG002. We assemble a single contig for each haplotype, align them to the reference, call phased small and structural variants, and define a small variant benchmark for the MHC, covering 94% of the MHC and 22368 variants smaller than 50 bp, 49% more variants than a mapping-based benchmark. This benchmark reliably identifies errors in mapping-based callsets, and enables performance assessment in regions with much denser, complex variation than regions covered by previous benchmarks.


Assuntos
Diploide , Complexo Principal de Histocompatibilidade/genética , Benchmarking , Linhagem Celular , Variação Genética , Genoma Humano , Haplótipos , Humanos
14.
Nat Commun ; 11(1): 4020, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782262

RESUMO

While variance components analysis has emerged as a powerful tool in complex trait genetics, existing methods for fitting variance components do not scale well to large-scale datasets of genetic variation. Here, we present a method for variance components analysis that is accurate and efficient: capable of estimating one hundred variance components on a million individuals genotyped at a million SNPs in a few hours. We illustrate the utility of our method in estimating and partitioning variation in a trait explained by genotyped SNPs (SNP-heritability). Analyzing 22 traits with genotypes from 300,000 individuals across about 8 million common and low frequency SNPs, we observe that per-allele squared effect size increases with decreasing minor allele frequency (MAF) and linkage disequilibrium (LD) consistent with the action of negative selection. Partitioning heritability across 28 functional annotations, we observe enrichment of heritability in FANTOM5 enhancers in asthma, eczema, thyroid and autoimmune disorders.


Assuntos
Variação Genética/genética , Genoma Humano/genética , Modelos Genéticos , Alelos , Frequência do Gene , Genótipo , Humanos , Desequilíbrio de Ligação , Herança Multifatorial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável
15.
Nat Commun ; 11(1): 4267, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32848148

RESUMO

While footprinting analysis of ATAC-seq data can theoretically enable investigation of transcription factor (TF) binding, the lack of a computational tool able to conduct different levels of footprinting analysis has so-far hindered the widespread application of this method. Here we present TOBIAS, a comprehensive, accurate, and fast footprinting framework enabling genome-wide investigation of TF binding dynamics for hundreds of TFs simultaneously. We validate TOBIAS using paired ATAC-seq and ChIP-seq data, and find that TOBIAS outperforms existing methods for bias correction and footprinting. As a proof-of-concept, we illustrate how TOBIAS can unveil complex TF dynamics during zygotic genome activation in both humans and mice, and propose how zygotic Dux activates cascades of TFs, binds to repeat elements and induces expression of novel genetic elements.


Assuntos
Sequenciamento de Cromatina por Imunoprecipitação/métodos , Fatores de Transcrição/metabolismo , Ativação Transcricional , Zigoto/metabolismo , Animais , Sítios de Ligação/genética , Desenvolvimento Embrionário/genética , Epigênese Genética , Feminino , Genoma Humano , Proteínas de Homeodomínio/metabolismo , Humanos , Cinética , Camundongos , Regiões Promotoras Genéticas , Estudo de Prova de Conceito , Ligação Proteica/genética , Especificidade da Espécie
16.
BMC Bioinformatics ; 21(1): 338, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32736515

RESUMO

BACKGROUND: Analysis of somatic mutations from tumor whole exomes has fueled discovery of novel cancer driver genes. However, ~ 98% of the genome is non-coding and includes regulatory elements whose normal cellular functions can be disrupted by mutation. Whole genome sequencing (WGS), on the other hand, allows for identification of non-coding somatic variation and expanded estimation of background mutation rates, yet fewer computational tools exist for specific interrogation of this space. RESULTS: We present MutEnricher, a flexible toolset for investigating somatic mutation enrichment in both coding and non-coding genomic regions from WGS data. MutEnricher contains two distinct modules for these purposes that provide customizable options for calculating sample- and feature-specific background mutation rates. Additionally, both MutEnricher modules calculate feature-level and local, or "hotspot," somatic mutation enrichment statistics. CONCLUSIONS: MutEnricher is a flexible software package for investigating somatic mutation enrichment that is implemented in Python, is freely available, can be efficiently parallelized, and is highly configurable to researcher's specific needs. MutEnricher is available online at https://github.com/asoltis/MutEnricher .


Assuntos
Genoma Humano , Mutação/genética , Neoplasias/genética , Software , Humanos , Regiões Promotoras Genéticas/genética , Sequenciamento Completo do Genoma
17.
Pan Afr Med J ; 36: 80, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32774639

RESUMO

The coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has become a pandemic. There is currently no vaccine or effective treatment for COVID-19. Early diagnosis and management is key to favourable outcomes. In order to prevent more widespread transmission of the virus, rapid detection and isolation of confirmed cases is of utmost importance. Real time reverse transcriptase polymerase chain reaction (RT-PCR) is currently the "gold standard" for the detection of SARS-COV-2. There are several challenges associated with this test from sample collection to processing and the longer turnaround time for the results to be available. More rapid and faster diagnostic tests that may produce results within minutes to a few hours will be instrumental in controlling the disease. Serological tests that detect specific antibodies to the virus may be such options. In this review, we extensively searched for studies that compared RT-PCR with serological tests for the diagnosis of COVID-19. We extracted the data from the various selected studies that compared the different tests and summarised the available evidence to determine which test is more appropriate especially in Africa. We also reviewed the current evidence and the challenges for the genome sequencing of SARS-COV-2 in Africa. Finally, we discuss the relevance of the different diagnostic tests and the importance of genome sequencing in identifying potential therapeutic options for the control of COVID-19 in Africa.


Assuntos
Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Genoma Humano , Pneumonia Viral/diagnóstico , África/epidemiologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/genética , Humanos , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Testes Sorológicos , Fatores de Tempo
18.
Nat Commun ; 11(1): 4330, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859912

RESUMO

Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.


Assuntos
Mutação , Neoplasias/genética , Oncogenes/genética , Caracteres Sexuais , Instabilidade Cromossômica , Exoma , Feminino , Genoma Humano , Instabilidade Genômica , Humanos , Modelos Logísticos , Masculino , Fases de Leitura Aberta , beta Catenina/genética
19.
Nat Commun ; 11(1): 3868, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32747648

RESUMO

Archaeological research documents major technological shifts among people who have lived in the southern tip of South America (South Patagonia) during the last thirteen millennia, including the development of marine-based economies and changes in tools and raw materials. It has been proposed that movements of people spreading culture and technology propelled some of these shifts, but these hypotheses have not been tested with ancient DNA. Here we report genome-wide data from 20 ancient individuals, and co-analyze it with previously reported data. We reveal that immigration does not explain the appearance of marine adaptations in South Patagonia. We describe partial genetic continuity since ~6600 BP and two later gene flows correlated with technological changes: one between 4700-2000 BP that affected primarily marine-based groups, and a later one impacting all <2000 BP groups. From ~2200-1200 BP, mixture among neighbors resulted in a cline correlated to geographic ordering along the coast.


Assuntos
DNA Antigo/análise , Fósseis , Fluxo Gênico , Genoma Humano/genética , Migração Humana , Arqueologia/métodos , Argentina , Osso e Ossos/metabolismo , Chile , DNA Mitocondrial/classificação , DNA Mitocondrial/genética , Variação Genética , Geografia , Humanos , Filogenia , Datação Radiométrica/métodos , Análise de Sequência de DNA/métodos , Dente/metabolismo
20.
Nat Commun ; 11(1): 4072, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792663

RESUMO

Cpf1-linked base editors broaden the targeting scope of programmable cytidine deaminases by recognizing thymidine-rich protospacer-adjacent motifs (PAM) without inducing DNA double-strand breaks (DSBs). Here we present an unbiased in vitro method for identifying genome-wide off-target sites of Cpf1 base editors via whole genome sequencing. First, we treat human genomic DNA with dLbCpf1-BE ribonucleoprotein (RNP) complexes, which convert C-to-U at on-target and off-target sites and, then, with a mixture of E. coli uracil DNA glycosylase (UDG) and DNA glycosylase-lyase Endonuclease VIII, which removes uracil and produces single-strand breaks (SSBs) in vitro. Whole-genome sequencing of the resulting digested genome (Digenome-seq) reveals that, on average, dLbCpf1-BE induces 12 SSBs in vitro per crRNA in the human genome. Off-target sites with an editing frequency as low as 0.1% are successfully identified by this modified Digenome-seq method, demonstrating its high sensitivity. dLbCpf1-BEs and LbCpf1 nucleases often recognize different off-target sites, calling for independent analysis of each tool.


Assuntos
Citidina/metabolismo , Endonucleases/metabolismo , Sequenciamento Completo do Genoma/métodos , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Citidina/genética , DNA/genética , DNA/metabolismo , Endonucleases/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Edição de Genes , Genoma Humano/genética , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , RNA Guia/genética
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