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1.
Mol Cell ; 82(1): 209-217.e7, 2022 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-34951964

RESUMO

Extrachromosomal circular DNA (eccDNA) is common in somatic tissue, but its existence and effects in the human germline are unexplored. We used microscopy, long-read DNA sequencing, and new analytic methods to document thousands of eccDNAs from human sperm. EccDNAs derived from all genomic regions and mostly contained a single DNA fragment, although some consisted of multiple fragments. The generation of eccDNA inversely correlates with the meiotic recombination rate, and chromosomes with high coding-gene density and Alu element abundance form the least eccDNA. Analysis of insertions in human genomes further indicates that eccDNA can persist in the human germline when the circular molecules reinsert themselves into the chromosomes. Our results suggest that eccDNA has transient and permanent effects on the germline. They explain how differences in the physical and genetic map might arise and offer an explanation of how Alu elements coevolved with genes to protect genome integrity against deleterious mutations producing eccDNA.


Assuntos
Cromossomos Humanos , DNA Circular/metabolismo , Meiose , Recombinação Genética , Espermatozoides/metabolismo , Elementos Alu , DNA Circular/genética , Evolução Molecular , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Masculino , Mutação
2.
Bioinformatics ; 39(1)2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36661298

RESUMO

SUMMARY: With the rapid expansion of the capabilities of the DNA sequencers throughout the different sequencing generations, the quantity of generated data has likewise increased. This evolution has also led to new bioinformatical methods, for which in silico data have become crucial when verifying the accuracy of a model or the robustness of a genomic analysis pipeline. Here, we present a multithreaded next-generation simulator for next-generation sequencing data (NGSNGS), which simulates reads faster than currently available methods and programs. NGSNGS can simulate reads with platform-specific characteristics based on nucleotide quality score profiles as well as including a post-mortem damage model which is relevant for simulating ancient DNA. The simulated sequences are sampled (with replacement) from a reference DNA genome, which can represent a haploid genome, polyploid assemblies or even population haplotypes and allows the user to simulate known variable sites directly. The program is implemented in a multithreading framework and is factors faster than currently available tools while extending their feature set and possible output formats. AVAILABILITY AND IMPLEMENTATION: The method and associated programs are released as open-source software, code and user manual are available at https://github.com/RAHenriksen/NGSNGS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Genoma , Software , Genômica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , DNA Antigo , Análise de Sequência de DNA/métodos
3.
Clin Transl Med ; 12(4): e817, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35474296

RESUMO

BACKGROUND: Extrachromosomal circular deoxyribonucleic acid (eccDNA) is evolving as a valuable biomarker, while little is known about its presence in urine. METHODS: Here, we report the discovery and analysis of urinary cell-free eccDNAs (ucf-eccDNAs) in healthy controls and patients with advanced chronic kidney disease (CKD) by Circle-Seq. RESULTS: Millions of unique ucf-eccDNAs were identified and comprehensively characterised. The ucf-eccDNAs are GC-rich. Most ucf-eccDNAs are less than 1000 bp and are enriched in four pronounced peaks at 207, 358, 553 and 732 bp. Analysis of the genomic distribution of ucf-eccDNAs shows that eccDNAs are found on all chromosomes but enriched on chromosomes 17, 19 and 20 with a high density of protein-coding genes, CpG islands, short interspersed transposable elements (SINEs) and simple repeat elements. Analysis of eccDNA junction sequences further suggests that microhomology and palindromic repeats might be involved in eccDNA formation. The ucf-eccDNAs in CKD patients are significantly higher than those in healthy controls. Moreover, eccDNA with miRNA genes is highly enriched in CKD ucf-eccDNA. CONCLUSIONS: This work discovers and provides the first deep characterisation of ucf-eccDNAs and suggests ucf-eccDNA as a valuable noninnvasive biomarker for urogenital disorder diagnosis and monitoring.


Assuntos
DNA Circular , Insuficiência Renal Crônica , Biomarcadores , DNA , DNA Circular/genética , Feminino , Genômica , Humanos , Masculino , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/genética
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