ArticleProceedings of the National Academy of Sciences of the United States of America2021
Single-molecule sequencing reveals a large population of long cell-free DNA molecules in maternal plasma.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed.
- Reappraising the topology of cell-free fetal DNA in maternal blood toward improved prenatal genetic diagnostics.Science advances · 2026Review
- First-trimester multi-modal cell-free DNA analysis for prediction of preterm and term preeclampsia.AJOG global reports · 2026Article
- Near-perfect genome sequencing in medical genetics.Nature genetics · 2026Review
- cfMethDB: A Comprehensive cfDNA Methylation Data Resource for Cancer Biomarkers.Genomics, proteomics & bioinformatics · 2026Article
- Long-read sequencing technologies and bioinformatics: a new perspective for decoding DNA methylation modifications.Journal of translational medicine · 2026Review
- The Importance of Clinical Acumen for Prenatal Diagnosis in an Increasingly Technological World.Prenatal diagnosis · 2026Article
- Long-read sequencing identifies aberrant fragmentation patterns linked to elevated cell-free DNA levels in cancer.Genome biology · 2026Article
- Holistic determination of ends of cfDNA molecules.Cell genomics · 2026Article
- cfGWAS reveal genetic basis of cell-free DNA end motifs.Nature communications · 2026Article
- Critical assessment of intratumor and low-biomass microbiome using long-read sequencing.bioRxiv : the preprint server for biology · 2026Article
- Detection of primary cancer types via fragment size selection in circulating cell-free extrachromosomal circular DNA.Genome medicine · 2026Article
- Advancements in Liquid Biopsy Technologies for Non-Invasive Detection of Placental Dysfunction and Perinatal Complications: Focus on cfDNA, cfRNA, and Extracellular Vesicles.Maternal-fetal medicine (Wolters Kluwer Health, Inc.) · 2026Review
- Long-read sequencing for cancer liquid biopsy: advancing precision oncology.Frontiers in oncology · 2026Review
- Review
- Early-stage lung adenocarcinoma affects DNA methylation and gene expression in adjacent tissues.EMBO reports · 2025Article
- Advancements in Prenatal Genetic Screening and Testing: Emerging Technologies and Evolving Applications.Diagnostics (Basel, Switzerland) · 2025Review
- Circulating Cell-free DNA Fragmentomics Detection and Beyond.Aging and disease · 2025Review
- Going Back in Time: Prenatal Presentations of Postnatal Genetic Diagnoses Made in a Neonatal Intensive Care Unit.Prenatal diagnosis · 2025Article
- Article
- Fragment dispersity index analysis of cfDNA fragments reveals chromatin accessibility and enables early cancer detection.Cell reports methods · 2025Article
4 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In the field of circulating cell-free DNA, most of the studies have focused on short DNA molecules (e.g., <500 bp). The existence of long cell-free DNA molecules has been poorly explored. In this study, we demonstrated that single-molecule real-time sequencing allowed us to detect and analyze a substantial proportion of long DNA molecules from both fetal and maternal sources in maternal plasma. Such molecules were beyond the size detection limits of short-read sequencing technologies. The proportions of long cell-free DNA molecules in maternal plasma over 500 bp were 15.5%, 19.8%, and 32.3% for the first, second, and third trimesters, respectively. The longest fetal-derived plasma DNA molecule observed was 23,635 bp. Long plasma DNA molecules demonstrated predominance of A or G 5' fragment ends. Pregnancies with preeclampsia demonstrated a reduction in long maternal plasma DNA molecules, reduced frequencies for selected 5' 4-mer end motifs ending with G or A, and increased frequencies for selected motifs ending with T or C. Finally, we have developed an approach that employs the analysis of methylation patterns of the series of CpG sites on a long DNA molecule for determining its tissue origin. This approach achieved an area under the curve of 0.88 in differentiating between fetal and maternal plasma DNA molecules, enabling the determination of maternal inheritance and recombination events in the fetal genome. This work opens up potential clinical utilities of long cell-free DNA analysis in maternal plasma including noninvasive prenatal testing of monogenic diseases and detection/monitoring of pregnancy-associated disorders such as preeclampsia.
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