Microhomology-mediated circular DNA formation from oligonucleosomal fragments during spermatogenesis

The landscape of extrachromosomal circular DNA (eccDNA) during mammalian spermatogenesis, as well as the biogenesis mechanism, remains to be explored. Here, we revealed widespread eccDNA formation in human sperms and mouse spermatogenesis. We noted that germline eccDNAs are derived from oligonucleos...

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Published in:eLife Vol. 12
Main Authors: Hu, Jun, Zhang, Zhe, Xiao, Sai, Cao, Yalei, Chen, Yinghong, Weng, Jiaming, Jiang, Hui, Li, Wei, Chen, Jia-Yu, Liu, Chao
Format: Journal Article
Language:English
Published: Cambridge eLife Sciences Publications Ltd 17.10.2023
eLife Sciences Publications, Ltd
Subjects:
Bioinformatics
Biosynthesis
Cell death
Circular DNA
Developmental Biology
DNA fragmentation
Euchromatin
extrachromosomal circular DNA
Genetics and Genomics
Genomes
Heterochromatin
Meiosis
microhomology
Mitochondrial DNA
Morphology
Quality control
Recombination hot spots
Sperm
Spermatogenesis
ISSN:2050-084X, 2050-084X
Online Access:Get full text
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Summary:The landscape of extrachromosomal circular DNA (eccDNA) during mammalian spermatogenesis, as well as the biogenesis mechanism, remains to be explored. Here, we revealed widespread eccDNA formation in human sperms and mouse spermatogenesis. We noted that germline eccDNAs are derived from oligonucleosomal DNA fragmentation in cells likely undergoing cell death, providing a potential new way for quality assessment of human sperms. Interestingly, small-sized eccDNAs are associated with euchromatin, while large-sized ones are preferentially generated from heterochromatin. By comparing sperm eccDNAs with meiotic recombination hotspots and structural variations, we found that they are barely associated with de novo germline deletions. We further developed a bioinformatics pipeline to achieve nucleotide-resolution eccDNA detection even with the presence of microhomologous sequences that interfere with precise breakpoint identification. Empowered by our method, we provided strong evidence to show that microhomology-mediated end joining is the major eccDNA biogenesis mechanism. Together, our results shed light on eccDNA biogenesis mechanism in mammalian germline cells.
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These authors contributed equally to this work.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.87115