Abstract
Trisomies 18 and 21 are the two most common live born autosomal aneuploidies in humans. While the anatomic abnormalities in affected fetuses are well documented, the dysregulated biological pathways associated with the development of the aneuploid phenotype are less clear. Amniotic fluid (AF) cell-free RNA is a valuable source of biological information obtainable from live fetuses. In this study, we mined gene expression data previously produced by our group from mid-trimester AF supernatant samples. We identified the euploid, trisomy 18 and trisomy 21 AF transcriptomes, and analyzed them with a particular focus on the nervous system. We used multiple bioinformatics resources, including DAVID, Ingenuity Pathway Analysis, and the BioGPS Gene Expression Atlas. Our analyses confirmed that AF supernatant from aneuploid fetuses is enriched for nervous system gene expression and neurological disease pathways. Tissue analysis showed that fetal brain cortex and Cajal–Retzius cells were significantly enriched for genes contained in the AF transcriptomes. We also examined AF transcripts known to be dysregulated in aneuploid fetuses compared with euploid controls and identified several brain-specific transcripts among them. Many of these genes play critical roles in nervous system development. NEUROD2, which was downregulated in trisomy 18, induces neurogenic differentiation. SOX11, downregulated in trisomy 21, is a transcription factor that is essential for pan-neuronal protein expression and axonal growth of sensory neurons. Our results show that whole transcriptome analysis of cell-free RNA in AF from live pregnancies permits discovery of biomarkers of abnormal human neurodevelopment and advances our understanding of the pathophysiology of aneuploidy.
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References
Altug-Teber O, Bonin M, Walter M, Mau-Holzmann UA, Dufke A, Stappert H, Tekesin I, Heilbronner H, Nieselt K, Riess O (2007) Specific transcriptional changes in human fetuses with autosomal trisomies. Cytogenet Genome Res 119(3–4):171–184
Bergsland M, Werme M, Malewicz M, Perlmann T, Muhr J (2006) The establishment of neuronal properties is controlled by Sox4 and Sox11. Gene Dev 20(24):3475–3486
Bianchi DW, Crombleholme TM, D’Alton ME, Malone FD (2010) Fetology, 2nd edn. McGraw-Hill Companies, Inc, USA, pp 910–925
Birk E, Har-Zahav A, Manzini CM, Pasmanik-Chor M, Kornreich L, Walsh CA, Noben-Trauth K, Albin A, Simon AJ, Colleaux L, Morad Y, Rainshtein L, Tischfield DJ, Wang P, Magal N, Maya I, Shoshani N, Rechavi G, Gothelf D, Maydan G, Shohat M, Basel-Vanagaite L (2010) SOBP is mutated in syndromic and nonsyndromic intellectual disability and is highly expressed in the brain limbic system. Am J Hum Genet 87(5):694–700
Bolstad BM (2004) Low level analysis of high-density oligonucleotide array data: background, normalization and summarization. University of California, Berkeley
Boon K, Osorio EC, Greenhut SF, Schaefer CF, Shoemaker J, Polyak K, Morin PJ, Buetow KH, Strausberg RL, De Souza SJ, Riggins GJ (2002) An anatomy of normal and malignant gene expression. Proc Natl Acad Sci USA 99(17):11287–11292
Chen Z, Montcouquiol M, Calderon R, Jenkins NA, Copeland NG, Kelley MW, Noben-Trauth K (2008) Jxc1/Sobp, encoding a nuclear zinc finger protein, is critical for cochlear growth, cell fate, and patterning of the organ of corti. J Neurosci 28(26):6633–6641
Chou CY, Liu LY, Chen CY, Tsai CH, Hwa HL, Chang LY, Lin YS, Hsieh FJ (2008) Gene expression variation increase in trisomy 21 tissues. Mamm Genome 19(6):398–405
Chung IH, Lee SH, Lee KW, Park SH, Cha KY, Kim NS, Yoo HS, Kim YS, Lee S (2005) Gene expression analysis of cultured amniotic fluid cell with Down syndrome by DNA microarray. J Korean Med Sci 20(1):82–87
Consortium U (2011) Ongoing and future developments at the Universal Protein Resource. Nucleic Acids Res 39((Database issue)):D214–D219
Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA (2003) DAVID: database for annotation, visualization, and integrated discovery. Genome Biol 4(5):P3
Franklin A, Kao A, Tapscott S, Unis A (2001) NeuroD homologue expression during cortical development in the human brain. J Child Neurol 16(11):849–853
Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, Hornik K, Hothorn T, Huber W, Iacus S, Irizarry R, Leisch F, Li C, Maechler M, Rossini AJ, Sawitzki G, Smith C, Smyth G, Tierney L, Yang JY, Zhang J (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5(10):R80
Hosack DA, Dennis G Jr, Sherman BT, Lane HC, Lempicki RA (2003) Identifying biological themes within lists of genes with EASE. Genome Biol 4(10):R70
Hui L, Bianchi DW (2011) Cell-free fetal nucleic acids in amniotic fluid. Hum Reprod Update 17(3):362–371
Hui L, Slonim DK, Wick HC, Johnson KL, Bianchi DW (2012) The amniotic fluid transcriptome: a source of novel information about human fetal development. Obstet Gynecol 119(1):111–118
Kida Y, Shiraishi T, Ogura T (2004) Identification of chick and mouse Daam1 and Daam2 genes and their expression patterns in the central nervous system. Brain Res Dev Brain Res 153(1):143–150
Kislinger T, Cox B, Kannan A, Chung C, Hu P, Ignatchenko A, Scott MS, Gramolini AO, Morris Q, Hallett MT, Rossant J, Hughes TR, Frey B, Emili A (2006) Global survey of organ and organelle protein expression in mouse: combined proteomic and transcriptomic profiling. Cell 125(1):173–186
Koide K, Slonim DK, Johnson KL, Tantravahi U, Cowan JM, Bianchi DW (2011) Transcriptomic analysis of cell-free fetal RNA suggests a specific molecular phenotype in trisomy 18. Hum Genet 129(3):295–305
Larrabee PB, Johnson KL, Lai C, Ordovas J, Cowan JM, Tantravahi U, Bianchi DW (2005) Global gene expression analysis of the living human fetus using cell-free messenger RNA in amniotic fluid. JAMA 293(7):836–842
Lin L, Lee VM, Wang Y, Lin JS, Sock E, Wegner M, Lei L (2011) Sox11 regulates survival and axonal growth of embryonic sensory neurons. Dev Dyn 240(1):52–64
Mattar P, Langevin LM, Markham K, Klenin N, Shivji S, Zinyk D, Schuurmans C (2008) Basic helix-loop-helix transcription factors cooperate to specify a cortical projection neuron identity. Mol Cell Biol 28(5):1456–1469
Michibata H, Okuno T, Konishi N, Kyono K, Wakimoto K, Aoki K, Kondo Y, Takata K, Kitamura Y, Taniguchi T (2009) Human GPM6A is associated with differentiation and neuronal migration of neurons derived from human embryonic stem cells. Stem Cells & Dev 18(4):629–639
Ravanpay AC, Hansen SJ, Olson JM (2010) Transcriptional inhibition of REST by NeuroD2 during neuronal differentiation. Mol Cell Neurosci 44(2):178–189
Slonim DK, Koide K, Johnson KL, Tantravahi U, Cowan JM, Jarrah Z, Bianchi DW (2009) Functional genomic analysis of amniotic fluid cell-free mRNA suggests that oxidative stress is significant in Down syndrome fetuses. Proc Natl Acad Sci USA 106(23):9425–9429
Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, Zhang J, Soden R, Hayakawa M, Kreiman G, Cooke MP, Walker JR, Hogenesch JB (2004) A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci USA 101(16):6062–6067
Vilardell M, Rasche A, Thormann A, Maschke-Dutz E, Perez-Jurado LA, Lehrach H, Herwig R (2011) Meta-analysis of heterogeneous Down syndrome data reveals consistent genome-wide dosage effects related to neurological processes. BMC Genomics 12:229
Woo J-M, Park SJ, Kang HI, Kim BG, Shim SB, Jee SW, Lee SH, Sin JS, Bae CJ, Jang MK, Cho C, Hwang DY, Kim CK (2010) Characterization of changes in global gene expression in the brain of neuron-specific enolase/human Tau23 transgenic mice in response to overexpression of Tau protein. Int J Mol Med 25(5):667–675
Acknowledgments
The authors thank Janet Cowan, PhD, and Uma Tantravahi, PhD, who provided the AF supernatant samples. Financial support was provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD 42053-09 to Dr Bianchi and R01 HD 058880 to Dr Slonim); the University of Sydney Medical School (Albert S. McKern Research Scholarship to Dr Hui); and the Royal Australian and New Zealand College of Obstetricians and Gynaecologists Research Foundation (Fotheringham Fellowship to Dr Hui). The authors declare that they have no conflicts of interest to disclose. This study complies with current laws of the United States of America.
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Hui, L., Slonim, D.K., Wick, H.C. et al. Novel neurodevelopmental information revealed in amniotic fluid supernatant transcripts from fetuses with trisomies 18 and 21. Hum Genet 131, 1751–1759 (2012). https://doi.org/10.1007/s00439-012-1195-x
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DOI: https://doi.org/10.1007/s00439-012-1195-x