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1.
Nature ; 596(7870): 43-53, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34349292

RESUMO

The genomes of virtually all organisms contain repetitive sequences that are generated by the activity of transposable elements (transposons). Transposons are mobile genetic elements that can move from one genomic location to another; in this process, they amplify and increase their presence in genomes, sometimes to very high copy numbers. In this Review we discuss new evidence and ideas that the activity of retrotransposons, a major subgroup of transposons overall, influences and even promotes the process of ageing and age-related diseases in complex metazoan organisms, including humans. Retrotransposons have been coevolving with their host genomes since the dawn of life. This relationship has been largely competitive, and transposons have earned epithets such as 'junk DNA' and 'molecular parasites'. Much of our knowledge of the evolution of retrotransposons reflects their activity in the germline and is evident from genome sequence data. Recent research has provided a wealth of information on the activity of retrotransposons in somatic tissues during an individual lifespan, the molecular mechanisms that underlie this activity, and the manner in which these processes intersect with our own physiology, health and well-being.


Assuntos
Envelhecimento/genética , Envelhecimento/patologia , Doença/genética , Retroelementos/genética , Animais , Dano ao DNA , Inativação Gênica , Genoma Humano/genética , Genômica , Humanos , Imunidade Inata
2.
Nat Commun ; 12(1): 4842, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376650

RESUMO

Nearby genes are often expressed as a group. Yet, the prevalence, molecular mechanisms and genetic control of local gene co-expression are far from being understood. Here, by leveraging gene expression measurements across 49 human tissues and hundreds of individuals, we find that local gene co-expression occurs in 13% to 53% of genes per tissue. By integrating various molecular assays (e.g. ChIP-seq and Hi-C), we estimate the ability of several mechanisms, such as enhancer-gene interactions, in distinguishing gene pairs that are co-expressed from those that are not. Notably, we identify 32,636 expression quantitative trait loci (eQTLs) which associate with co-expressed gene pairs and often overlap enhancer regions. Due to affecting several genes, these eQTLs are more often associated with multiple human traits than other eQTLs. Our study paves the way to comprehend trait pleiotropy and functional interpretation of QTL and GWAS findings. All local gene co-expression identified here is available through a public database ( https://glcoex.unil.ch/ ).


Assuntos
Regulação da Expressão Gênica , Pleiotropia Genética/genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Sítios de Ligação/genética , Ontologia Genética , Estudos de Associação Genética/métodos , Humanos , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição/metabolismo
3.
Nat Commun ; 12(1): 4897, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385432

RESUMO

Precise control of mammalian gene expression is facilitated through epigenetic mechanisms and nuclear organization. In particular, insulated chromosome structures are important for regulatory control, but the phenotypic consequences of their boundary disruption on developmental processes are complex and remain insufficiently understood. Here, we generated deeply sequenced Hi-C data for human pluripotent stem cells (hPSCs) that allowed us to identify CTCF loop domains that have highly conserved boundary CTCF sites and show a notable enrichment of individual developmental regulators. Importantly, perturbation of such a boundary in hPSCs interfered with proper differentiation through deregulated distal enhancer-promoter activity. Finally, we found that germline variations affecting such boundaries are subject to purifying selection and are underrepresented in the human population. Taken together, our findings highlight the importance of developmental gene isolation through chromosomal folding structures as a mechanism to ensure their proper expression.


Assuntos
Diferenciação Celular/genética , Perfilação da Expressão Gênica/métodos , Genoma Humano/genética , Células-Tronco Embrionárias Humanas/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Elementos Reguladores de Transcrição/genética , Sítios de Ligação/genética , Western Blotting , Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Linhagem Celular , Elementos Facilitadores Genéticos/genética , Células-Tronco Embrionárias Humanas/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Regiões Promotoras Genéticas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA/métodos
4.
Prog Mol Subcell Biol ; 60: 203-234, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34386877

RESUMO

Here we present three interesting novel human Higher-Order Repeats (HORs) discovered using the HOR-searching method with GRM algorithm: (a) The novel Neuroblastoma Breakpoint Family gene (NBPF) 3mer HOR, discovered applying GRM algorithm to human chromosome 1 (Paar et al., Mol Biol Evol 28:1877-1892, 2011). NBPF 3mer HOR is based on previously known ~1.6 kb NBPF primary repeat monomers (known as DUF1220 domain) in human chromosome 1, but the NBPF HOR was not known before its discovery by using GRM. It should be stressed that the NBPF HOR presents a unique human-specific pattern, distinguishing human from nonhuman primates. (b) The novel quartic HOR (2mer⊃2mer⊃9mer) discovered using the GRM algorithm for analysis of hornerin genes in human chromosome 1 (Paar et al., Mol Biol Evol 28:1877-1892, 2011). This quartic HOR is based on 39 bp hornerin primary repeat monomer in human chromosome 1. To our knowledge, this is the first known case of quartic HOR, with four levels of hierarchy of HOR organization. (c) The novel 33mer alpha satellite HOR in human chromosome 21, discovered using the GRM algorithm (Gluncic et al., Sci Rep 9:12629, 2019). This 33mer HOR in the smallest human chromosome is the largest alpha satellite HOR copy among all 22 somatic human chromosomes. Moreover, the same 33mer HOR is present in the hg38 human genome assembly of four human chromosomes: 21, 22, 13, and 14. We point out that the DUF1220 encoding genomic structures in NBPF genes in human chromosome 1, recently studied and related to the brain evolution and pathologies and cognitive aptitude, can be considered in the framework of the general concept of HORs, already extensively studied in genomics, especially in the centromeric region.


Assuntos
Cromossomos Humanos Par 21 , Neuroblastoma , Animais , Centrômero , DNA Satélite , Éxons , Genoma Humano/genética , Humanos , Neuroblastoma/genética
5.
Comput Biol Chem ; 93: 107538, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34246892

RESUMO

Nowadays, the purpose of human genomics is widely emerging in health-related problems and also to achieve time and cost-efficient healthcare. Due to advancement in genomics and its research, development in privacy concerns is needed regarding querying, accessing and, storage and computation of the genomic data. While the genomic data is widely accessible, the privacy issues may emerge due to the untrusted third party (adversaries/researchers), they may reveal the information or strategy plans regarding the genome data of an individual when it is requested for research purposes. To mitigate this problem many privacy-preserving techniques are used along with cryptographic methods are briefly discussed. Furthermore, efficiency and accuracy in a secure and private genomic data computation are needed to be researched in future.


Assuntos
Segurança Computacional , Bases de Dados Genéticas , Privacidade Genética , Genoma Humano/genética , Inquéritos e Questionários , Humanos
6.
Mol Cell ; 81(14): 2873-2874, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34270943

RESUMO

Wang et al. (2021) comprehensively map DNA replication initiation events across the human genome using single-molecule optical resolution mapping and find that initiation events are randomly distributed across broad initiation zones that are only utilized in a stochastic fashion across a population of cells.


Assuntos
Genoma Humano , Origem de Replicação , Replicação do DNA , Genoma Humano/genética , Humanos , Origem de Replicação/genética
7.
Commun Biol ; 4(1): 830, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215845

RESUMO

Genome-wide identification of DNA double-strand breaks (DSBs) induced by CRISPR-associated protein (Cas) systems is vital for profiling the off-target events of Cas nucleases. However, current methods for off-target discovery are tedious and costly, restricting their widespread applications. Here we present an easy alternative method for CRISPR off-target detection by tracing the integrated oligonucleotide Tag using next-generation-sequencing (CRISPR-Tag-seq, or Tag-seq). Tag-seq enables rapid and convenient profiling of nuclease-induced DSBs by incorporating the optimized double-stranded oligodeoxynucleotide sequence (termed Tag), adapters, and PCR primers. Moreover, we employ a one-step procedure for library preparation in Tag-seq, which can be applied in the routine workflow of a molecular biology laboratory. We further show that Tag-seq successfully determines the cleavage specificity of SpCas9 variants and Cas12a/Cpf1 in a large-scale manner, and discover the integration sites of exogenous genes introduced by the Sleeping Beauty transposon. Our results demonstrate that Tag-seq is an efficient and scalable approach to genome-wide identification of Cas-nuclease-induced off-targets.


Assuntos
Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas , Quebras de DNA de Cadeia Dupla , Edição de Genes/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Proteína 9 Associada à CRISPR/genética , DNA/genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Oligodesoxirribonucleotídeos/genética , Reprodutibilidade dos Testes
8.
Mol Cell ; 81(16): 3422-3439.e11, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34320405

RESUMO

Maturation of canonical microRNA (miRNA) is initiated by DROSHA that cleaves the primary transcript (pri-miRNA). More than 1,800 miRNA loci are annotated in humans, but it remains largely unknown whether and at which sites pri-miRNAs are cleaved by DROSHA. Here, we performed in vitro processing on a full set of human pri-miRNAs (miRBase version 21) followed by sequencing. This comprehensive profiling enabled us to classify miRNAs on the basis of DROSHA dependence and map their cleavage sites with respective processing efficiency measures. Only 758 pri-miRNAs are confidently processed by DROSHA, while the majority may be non-canonical or false entries. Analyses of the DROSHA-dependent pri-miRNAs show key cis-elements for processing. We observe widespread alternative processing and unproductive cleavage events such as "nick" or "inverse" processing. SRSF3 is a broad-acting auxiliary factor modulating alternative processing and suppressing unproductive processing. The profiling data and methods developed in this study will allow systematic analyses of miRNA regulation.


Assuntos
MicroRNAs/genética , Processamento Pós-Transcricional do RNA/genética , Ribonuclease III/genética , Fatores de Processamento de Serina-Arginina/genética , Sítios de Ligação/genética , Genoma Humano/genética , Células HEK293 , Humanos , Interferência de RNA
9.
Nature ; 594(7863): 356-364, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34135521

RESUMO

In less than a decade, analyses of ancient genomes have transformed our understanding of the Indigenous peopling and population history of the Americas. These studies have shown that this history, which began in the late Pleistocene epoch and continued episodically into the Holocene epoch, was far more complex than previously thought. It is now evident that the initial dispersal involved the movement from northeast Asia of distinct and previously unknown populations, including some for whom there are no currently known descendants. The first peoples, once south of the continental ice sheets, spread widely, expanded rapidly and branched into multiple populations. Their descendants-over the next fifteen millennia-experienced varying degrees of isolation, admixture, continuity and replacement, and their genomes help to illuminate the relationships among major subgroups of Native American populations. Notably, all ancient individuals in the Americas, save for later-arriving Arctic peoples, are more closely related to contemporary Indigenous American individuals than to any other population elsewhere, which challenges the claim-which is based on anatomical evidence-that there was an early, non-Native American population in the Americas. Here we review the patterns revealed by ancient genomics that help to shed light on the past peoples who created the archaeological landscape, and together lead to deeper insights into the population and cultural history of the Americas.


Assuntos
Genética Populacional , Genoma Humano , Genômica , Mapeamento Geográfico , Migração Humana/história , América , Arqueologia , Genoma Humano/genética , História Antiga , Humanos , Ilhas do Pacífico , Polimorfismo de Nucleotídeo Único/genética
10.
IEEE Pulse ; 12(3): 11-13, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34156927

RESUMO

At a time when a global vaccine program is being rolled out at unprecedented speed, the world is more aware than ever before of the wonders of medical science. There are, however, many diseases that remain beyond the reach of modern medicine and the potency of some of our most widely used therapies are waning.


Assuntos
Terapia Biológica , Edição de Genes , Proteoma/genética , Genoma Humano/genética , Humanos
11.
Mol Cell ; 81(14): 2975-2988.e6, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34157308

RESUMO

The heterogeneous nature of eukaryotic replication kinetics and the low efficiency of individual initiation sites make mapping the location and timing of replication initiation in human cells difficult. To address this challenge, we have developed optical replication mapping (ORM), a high-throughput single-molecule approach, and used it to map early-initiation events in human cells. The single-molecule nature of our data and a total of >2,500-fold coverage of the human genome on 27 million fibers averaging ∼300 kb in length allow us to identify initiation sites and their firing probability with high confidence. We find that the distribution of human replication initiation is consistent with inefficient, stochastic activation of heterogeneously distributed potential initiation complexes enriched in accessible chromatin. These observations are consistent with stochastic models of initiation-timing regulation and suggest that stochastic regulation of replication kinetics is a fundamental feature of eukaryotic replication, conserved from yeast to humans.


Assuntos
Replicação do DNA/genética , Células Eucarióticas/fisiologia , Genoma Humano/genética , Linhagem Celular Tumoral , Cromatina/genética , Período de Replicação do DNA/genética , Genoma Fúngico/genética , Estudo de Associação Genômica Ampla/métodos , Células HeLa , Humanos , Origem de Replicação/genética , Saccharomyces cerevisiae/genética , Sítio de Iniciação de Transcrição/fisiologia
13.
Genes (Basel) ; 12(5)2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069634

RESUMO

Variability is the source on which selective pressure acts, allowing genome evolution and adaptation [...].


Assuntos
Genes/genética , Genoma Humano/genética , Adaptação Fisiológica/genética , Animais , Evolução Molecular , Humanos , Fenótipo , Plantas/genética
14.
Curr Biol ; 31(16): 3504-3514.e9, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34171302

RESUMO

The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has emphasized the vulnerability of human populations to novel viral pressures, despite the vast array of epidemiological and biomedical tools now available. Notably, modern human genomes contain evolutionary information tracing back tens of thousands of years, which may help identify the viruses that have impacted our ancestors-pointing to which viruses have future pandemic potential. Here, we apply evolutionary analyses to human genomic datasets to recover selection events involving tens of human genes that interact with coronaviruses, including SARS-CoV-2, that likely started more than 20,000 years ago. These adaptive events were limited to the population ancestral to East Asian populations. Multiple lines of functional evidence support an ancient viral selective pressure, and East Asia is the geographical origin of several modern coronavirus epidemics. An arms race with an ancient coronavirus, or with a different virus that happened to use similar interactions as coronaviruses with human hosts, may thus have taken place in ancestral East Asian populations. By learning more about our ancient viral foes, our study highlights the promise of evolutionary information to better predict the pandemics of the future. Importantly, adaptation to ancient viral epidemics in specific human populations does not necessarily imply any difference in genetic susceptibility between different human populations, and the current evidence points toward an overwhelming impact of socioeconomic factors in the case of coronavirus disease 2019 (COVID-19).


Assuntos
Infecções por Coronavirus/história , Coronavirus/genética , Genoma Humano/genética , Interações entre Hospedeiro e Microrganismos/genética , Pandemias/história , Infecções por Coronavirus/virologia , Conjuntos de Dados como Assunto , Evolução Molecular , Extremo Oriente/epidemiologia , Frequência do Gene , Predisposição Genética para Doença , Genoma Viral/genética , Estudo de Associação Genômica Ampla , História Antiga , Projeto Genoma Humano , Humanos , Mutação , Filogenia , Seleção Genética
16.
Virus Res ; 302: 198466, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34087261

RESUMO

Vigorous vaccination programs against SARS-CoV-2-causing Covid-19 are the major chance to fight this dreadful pandemic. The currently administered vaccines depend on adenovirus DNA vectors or on SARS-CoV-2 mRNA that might become reverse transcribed into DNA, however infrequently. In some societies, people have become sensitized against the potential short- or long-term side effects of foreign DNA being injected into humans. In my laboratory, the fate of foreign DNA in mammalian (human) cells and organisms has been investigated for many years. In this review, a summary of the results obtained will be presented. This synopsis has been put in the evolutionary context of retrotransposon insertions into pre-human genomes millions of years ago. In addition, studies on adenovirus vector-based DNA, on the fate of food-ingested DNA as well as the long-term persistence of SARS-CoV-2 RNA/DNA will be described. Actual integration of viral DNA molecules and of adenovirus vector DNA will likely be chance events whose frequency and epigenetic consequences cannot with certainty be assessed. The review also addresses problems of remaining adenoviral gene expression in adenoviral-based vectors and their role in side effects of vaccines. Eventually, it will come down to weighing the possible risks of genomic insertions of vaccine-associated foreign DNA and unknown levels of vector-carried adenoviral gene expression versus protection against the dangers of Covid-19. A decision in favor of vaccination against life-threatening disease appears prudent. Informing the public about the complexities of biology will be a reliable guide when having to reach personal decisions about vaccinations.


Assuntos
Adenoviridae/genética , Vacinas contra COVID-19/genética , COVID-19/prevenção & controle , Genoma Humano/genética , Pandemias , SARS-CoV-2/imunologia , Vacinação , COVID-19/epidemiologia , COVID-19/virologia , DNA Viral/genética , Expressão Gênica , Vetores Genéticos/genética , Humanos , RNA Mensageiro/genética , RNA Viral/genética , SARS-CoV-2/genética
18.
Nat Commun ; 12(1): 3836, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158502

RESUMO

Transposable elements (TEs) help shape the structure and function of the human genome. When inserted into some locations, TEs may disrupt gene regulation and cause diseases. Here, we present xTea (x-Transposable element analyzer), a tool for identifying TE insertions in whole-genome sequencing data. Whereas existing methods are mostly designed for short-read data, xTea can be applied to both short-read and long-read data. Our analysis shows that xTea outperforms other short read-based methods for both germline and somatic TE insertion discovery. With long-read data, we created a catalogue of polymorphic insertions with full assembly and annotation of insertional sequences for various types of retroelements, including pseudogenes and endogenous retroviruses. Notably, we find that individual genomes have an average of nine groups of full-length L1s in centromeres, suggesting that centromeres and other highly repetitive regions such as telomeres are a significant yet unexplored source of active L1s. xTea is available at https://github.com/parklab/xTea .


Assuntos
Elementos de DNA Transponíveis/genética , Genoma Humano/genética , Genômica/métodos , Mutagênese Insercional , Sequenciamento Completo do Genoma/métodos , Rearranjo Gênico , Variação Genética , Haplótipos , Humanos , Anotação de Sequência Molecular/métodos , Pseudogenes/genética
19.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065521

RESUMO

Music is an exclusive feature of humankind. It can be considered as a form of universal communication, only partly comparable to the vocalizations of songbirds. Many trends of research in this field try to address music origins, as well as the genetic bases of musicality. On one hand, several hypotheses have been made on the evolution of music and its role, but there is still debate, and comparative studies suggest a gradual evolution of some abilities underlying musicality in primates. On the other hand, genome-wide studies highlight several genes associated with musical aptitude, confirming a genetic basis for different musical skills which humans show. Moreover, some genes associated with musicality are involved also in singing and song learning in songbirds, suggesting a likely evolutionary convergence between humans and songbirds. This comprehensive review aims at presenting the concept of music as a sociocultural manifestation within the current debate about its biocultural origin and evolutionary function, in the context of the most recent discoveries related to the cross-species genetics of musical production and perception.


Assuntos
Genoma Humano/genética , Animais , Evolução Biológica , Genômica/métodos , Humanos , Música
20.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071577

RESUMO

Open chromatin regions (OCRs) are special regions of the human genome that can be accessed by DNA regulatory elements. Several studies have reported that a series of OCRs are associated with mechanisms involved in human diseases, such as cancers. Identifying OCRs using ATAC-seq or DNase-seq is often expensive. It has become popular to detect OCRs from plasma cell-free DNA (cfDNA) sequencing data, because both the fragmentation modes of cfDNA and the sequencing coverage in OCRs are significantly different from those in other regions. However, it is a challenging computational problem to accurately detect OCRs from plasma cfDNA-seq data, as multiple factors-e.g., sequencing and mapping bias, insufficient read depth, etc.-often mislead the computational model. In this paper, we propose a novel bioinformatics pipeline, OCRDetector, for detecting OCRs from whole-genome cfDNA sequencing data. The pipeline calculates the window protection score (WPS) waveform and the cfDNA sequencing coverage. To validate the proposed pipeline, we compared the percentage overlap of our OCRs with those obtained by other methods. The experimental results show that 81% of the TSS regions of housekeeping genes are detected, and our results have obvious tissue specificity. In addition, the overlap percentage between our OCRs and the high-confidence OCRs obtained by ATAC-seq or DNase-seq is greater than 70%.


Assuntos
Ácidos Nucleicos Livres/genética , Cromatina/genética , Biologia Computacional/métodos , Genoma Humano/genética , Sequências Reguladoras de Ácido Nucleico/genética , Sequenciamento Completo do Genoma/métodos , Ácidos Nucleicos Livres/sangue , Sequenciamento de Cromatina por Imunoprecipitação , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Reprodutibilidade dos Testes , Análise de Sequência de DNA
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