title: Noninvasive in vivo monitoring of tissue-specific global gene expression in humans.
abstract: Circulating cell-free RNA in the blood provides a potential window into the health, phenotype, and developmental programs of a variety of human organs. We used high-throughput methods of RNA analysis such as microarrays and next-generation sequencing to characterize the global landscape circulating RNA in a cohort of human subjects. By focusing on genes whose expression is highly specific to certain tissues, we were able to identify the relative contributions of these tissues to circulating RNA and to monitor changes in tissue development and health. As one application of this approach, we performed a longitudinal study on pregnant women and analyzed their combined cell-free RNA transcriptomes across all three trimesters of pregnancy and after delivery. In addition to the analysis of mRNA, we observed and characterized noncoding species such as long noncoding RNA and circular RNA transcripts whose presence had not been previously observed in human plasma. We demonstrate that it is possible to track specific longitudinal phenotypic changes in both the mother and the fetus and that it is possible to directly measure transcripts from a variety of fetal tissues in the maternal blood sample. We also studied the role of neuron-specific transcripts in the blood of healthy adults and those suffering from the neurodegenerative disorder Alzheimer's disease and showed that disease specific neural transcripts are present at increased levels in the blood of affected individuals. Characterization of the cell-free transcriptome in its entirety may thus provide broad insights into human health and development without the need for invasive tissue sampling.
authors.affiliation: Departments of Bioengineering and.
authors.forename: Winston
authors.initials: W
authors.lastname: Koh
authors.affiliation: Departments of Bioengineering and.
authors.forename: Wenying
authors.initials: W
authors.lastname: Pan
authors.affiliation: Departments of Bioengineering and.
authors.forename: Charles
authors.initials: C
authors.lastname: Gawad
authors.affiliation: Departments of Bioengineering and.
authors.forename: H Christina
authors.initials: HC
authors.lastname: Fan
authors.affiliation: Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305; and.
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Kerchner
authors.affiliation: Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305; and.
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Yair J
authors.initials: YJ
authors.lastname: Blumenfeld
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Yasser Y
authors.initials: YY
authors.lastname: El-Sayed
authors.affiliation: Departments of Bioengineering and quake@stanford.edu.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Quake
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000097:blood; D017209:Apoptosis; D001921:Brain / Q000196:embryology / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D018507:Gene Expression Regulation, Developmental; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D019636:Neurodegenerative Diseases / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D012313:RNA / Q000097:blood*; D000079962:RNA, Circular; D013997:Time Factors; D059467:Transcriptome
chemical_list: D000079962:RNA, Circular; D012313:RNA
keywords: cell-free nucleic acids; genomics; noninvasive diagnostics