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1.
J Transl Med ; 20(1): 536, 2022 11 18.
Article in English | MEDLINE | ID: mdl-36401256

ABSTRACT

BACKGROUND: Chromosomal aneuploidy is the most common birth defect. However, the developmental mechanism and gene expression profile of fetuses with chromosomal aneuploidy are relatively unknown, and the maternal immune changes induced by fetal aneuploidy remain unclear. The inability to obtain the placenta multiple times in real-time is a bottleneck in research on aneuploid pregnancies. Plasma cell-free DNA (cfDNA) carries the gene expression profile information of its source cells and may be used to evaluate the development of fetuses with aneuploidy and the immune changes induced in the mother owing to fetal aneuploidy. METHODS: Here, we carried out whole-genome sequencing of the plasma cfDNA of 101 pregnant women carrying a fetus with trisomy (trisomy 21, n = 42; trisomy 18, n = 28; trisomy 13, n = 31) based on non-invasive prenatal testing (NIPT) screening and 140 normal pregnant women to identify differential genes according to the cfDNA nucleosome profile in the region around the transcription start sites (TSSs). RESULTS: The plasma cfDNA promoter profiles were found to differ between aneuploid and euploid pregnancies. A total of 158 genes with significant differences were identified, of which 43 genes were upregulated and 98 genes were downregulated. Functional enrichment and signaling pathway analysis were performed based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases found that these signal pathways were mainly related to the coordination of developmental signals during embryonic development, the control of cell growth and development, regulation of neuronal survival, and immune regulation, such as the MAPK, Hippo, TGF-ß, and Rap1 signaling pathways, which play important roles in the development of embryonic tissues and organs. Furthermore, based on the results of differential gene analysis, a total of 14 immune-related genes with significant differences from the ImmPort database were collected and analyzed. These significantly different immune genes were mainly associated with the maintenance of embryonic homeostasis and normal development. CONCLUSIONS: These results suggest that the distribution characteristics of cfDNA nucleosomes in maternal plasma can be used to reflect the status of fetal development and changes of the immune responses in trisomic pregnancies. Overall, our findings may provide research ideas for non-invasive detection of the physiological and pathological states of other diseases.


Subject(s)
Cell-Free Nucleic Acids , Nucleosomes , Humans , Female , Pregnancy , Nucleosomes/genetics , Nucleosomes/metabolism , Transcriptome , Aneuploidy , Fetus/metabolism , Trisomy , Cell-Free Nucleic Acids/genetics
2.
Prenat Diagn ; 42(8): 1008-1014, 2022 07.
Article in English | MEDLINE | ID: mdl-35441712

ABSTRACT

OBJECTIVE: To decrease the false-positive rate of NIPT using cell-free fetal DNA (cffDNA) fraction enrichment and the simulated confined placental mosaicism proportion (SCPMP) threshold application via cffDNA quantification. METHOD: Using a cffDNA enrichment method, 303 plasma samples with positive NIPT results (Z-score > 3.0; 200 true-positive and 103 false-positive cases) were re-sequenced. A method to calculate the SCPMP based on the quantified cffDNA fraction was developed; the SCPMP threshold between true- and false-positive NIPT results was determined and used for re-analyses. RESULTS: With enrichment, the fetal fraction of the 303 samples was 26.9 ± 8.4%, compared to 11.0 ± 3.2% without enrichment. The optimized threshold method with double determination using the Z-value-defined SCPMP can reduce the false-positive rates for trisomies 21, 18, and 13 by 87%, 80%, and 88.9%, respectively. CONCLUSION: Our optimized method can decrease the false-positive rate of NIPT results.


Subject(s)
Cell-Free Nucleic Acids , Cell-Free Nucleic Acids/genetics , DNA , Female , Humans , Mosaicism , Placenta , Pregnancy , Prenatal Diagnosis/methods
3.
Front Med (Lausanne) ; 8: 684238, 2021.
Article in English | MEDLINE | ID: mdl-34926480

ABSTRACT

Cell-free DNA (cfDNA) serves as a footprint of the nucleosome occupancy status of transcription start sites (TSSs), and has been subject to wide development for use in noninvasive health monitoring and disease detection. However, the requirement for high sequencing depth limits its clinical use. Here, we introduce a deep-learning pipeline designed for TSS coverage profiles generated from shallow cfDNA sequencing called the Autoencoder of cfDNA TSS (AECT) coverage profile. AECT outperformed existing single-cell sequencing imputation algorithms in terms of improvements to TSS coverage accuracy and the capture of latent biological features that distinguish sex or tumor status. We built classifiers for the detection of breast and rectal cancer using AECT-imputed shallow sequencing data, and their performance was close to that achieved by high-depth sequencing, suggesting that AECT could provide a broadly applicable noninvasive screening approach with high accuracy and at a moderate cost.

4.
Am J Obstet Gynecol ; 224(3): 300.e1-300.e9, 2021 03.
Article in English | MEDLINE | ID: mdl-32871130

ABSTRACT

BACKGROUND: Noninvasive monitoring of fetal development and the early detection of pregnancy-associated complications is challenging, largely because of the lack of information about the molecular spectrum during pregnancy. Recently, cell-free DNA in plasma was found to reflect the global nucleosome footprint and status of gene expression and showed potential for noninvasive health monitoring during pregnancy. OBJECTIVE: We aimed to test the relationships between plasma cell-free DNA profiles and pregnancy biology and evaluate the use of a cell-free DNA profile as a noninvasive method for physiological and pathologic status monitoring during pregnancy. STUDY DESIGN: We used genome cell-free DNA sequencing data generated from noninvasive prenatal testing in a total of 2937 pregnant women. For each physiological and pathologic condition, features of the cell-free DNA profile were identified using the discovery cohort, and support vector machine classifiers were built and evaluated using independent training and validation cohorts. RESULTS: We established nucleosome occupancy profiles at transcription start sites in different gestational trimesters, demonstrated the relationships between gene expression and cell-free DNA coverage at transcription start sites, and showed that the cell-free DNA profiles at transcription start sites represented the biological processes of pregnancy. In addition, using cell-free DNA data, nucleosome profiles of transcription factor binding sites were identified to reflect the transcription factor footprint, which may help to reveal the molecular mechanisms underlying pregnancy. Finally, by using machine-learning models on low-coverage noninvasive prenatal testing data, we evaluated the use of cell-free DNA nucleosome profiles for distinguishing gestational trimesters, fetal sex, and fetal trisomy 21 and highlighted its potential utility for predicting physiological and pathologic fetal conditions by using low-coverage noninvasive prenatal testing data. CONCLUSION: Our analyses profiled nucleosome footprints and regulatory networks during pregnancy and established a noninvasive proof-of-principle methodology for health monitoring during pregnancy.


Subject(s)
Gene Expression , Noninvasive Prenatal Testing , Pregnancy Complications/blood , Pregnancy Complications/genetics , Adolescent , Adult , Female , Humans , Middle Aged , Pregnancy , Proof of Concept Study , Young Adult
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