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Cited by 166Down syndrome and intellectual disability researchGenomic variations and chromosomal abnormalitiesGenetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities

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Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart

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Mao, Rong, Wang, Xiaowen, Spitznagel, Edward L, Frelin, Laurence P, Ting, Jason C, Ding, Huashi, Kim, Jung-whan, Ruczinski, Ingo, Downey, Thomas J, Pevsner, Jonathan·2005·Genome Biology
DOI 10.1186/gb-2005-6-13-r107PMC PMC1414106
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Abstract

Background: Down syndrome, caused by trisomic chromosome 21, is the leading genetic cause of mental retardation. Recent studies demonstrated that dosage-dependent increases in chromosome 21 gene expression occur in trisomy 21. However, it is unclear whether the entire transcriptome is disrupted, or whether there is a more restricted increase in the expression of those genes assigned to chromosome 21. Also, the statistical significance of differentially expressed genes in human Down syndrome tissues has not been reported. Results: We measured levels of transcripts in human fetal cerebellum and heart tissues using DNA microarrays and demonstrated a dosage-dependent increase in transcription across different tissue/cell types as a result of trisomy 21. Moreover, by having a larger sample size, combining the data from four different tissue and cell types, and using an ANOVA approach, we identified individual genes with significantly altered expression in trisomy 21, some of which showed this dysregulation in a tissue-specific manner. We validated our microarray data by over 5,600 quantitative real-time PCRs on 28 genes assigned to chromosome 21 and other chromosomes. Gene expression values from chromosome 21, but not from other chromosomes, accurately classified trisomy 21 from euploid samples. Our data also indicated functional groups that might be perturbed in trisomy 21. Conclusions: In Down syndrome, there is a primary transcriptional effect of disruption of chromosome 21 gene expression, without a pervasive secondary effect on the remaining transcriptome. The identification of dysregulated genes and pathways suggests molecular changes that may underlie the Down syndrome phenotypes.

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Crossref · 10.1186/gb-2005-6-13-r107

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Figure 1 PCA was used to visually assess the major sources of variation in the expression data. For each of the four panels, each data point represents a sample; there are 25 samples total. (a) PCA applied to chromosome 21 genes. The x-axis represents the first PC (accounting for 41% of the variance) and the y-axis represents the second PC (accounting for 21.2%). The graph is based on expression values for all 253 probe sets assigned to chromosome 21. This showed that the largest source of variability was due to tissue/cell type, accounting for 62.2% of the variance in the data. (b) PCA applied to chromosome 21 genes. The x-axis corresponds to the third PC, and the y-axis corresponds to the second PC. The third PC showed a separation of trisomic from euploid samples based on gene expression, accounting for 17.2% of the variance in the data. (c) PCA applied to non-chromosome 21 genes. The first two PCs (x- and y-axis) using expression values for genes assigned to all other chromosomes also showed that the largest source of variance was due to tissue (77.4% of total variance). These observations are similar to the results in panel a. (d) PCA applied to non-chromosome 21 genes. The x- and y-axis correspond to the third and second PCs, respectively. In contrast to the results of panel b, the third PC failed to show separation of trisomic from euploid samples (6.9% of total variance). The ellipsoids represent three standard deviations beyond the centroid of each tissue group. Data points correspond to samples (red, Down syndrome; blue, euploid) within a group (cerebrum, diamond symbols on data points, and green ellipsoid; cerebellum, square symbols on data points and blue ellipsoid; astrocyte, triangle symbols on data points and red ellipsoid; heart, hexagon symbols on data points and orange ellipsoid).
Figure 1 PCA was used to visually assess the major sources of variation in the expression data. For each of the four panels, each data point represents a sample; there are 25 samples total. (a) PCA applied to chromosome 21 genes. The x-axis represents the first PC (accounting for 41% of the variance) and the y-axis represents the second PC (accounting for 21.2%). The graph is based on expression values for all 253 probe sets assigned to chromosome 21. This showed that the largest source of variability was due to tissue/cell type, accounting for 62.2% of the variance in the data. (b) PCA applied to chromosome 21 genes. The x-axis corresponds to the third PC, and the y-axis corresponds to the second PC. The third PC showed a separation of trisomic from euploid samples based on gene expression, accounting for 17.2% of the variance in the data. (c) PCA applied to non-chromosome 21 genes. The first two PCs (x- and y-axis) using expression values for genes assigned to all other chromosomes also showed that the largest source of variance was due to tissue (77.4% of total variance). These observations are similar to the results in panel a. (d) PCA applied to non-chromosome 21 genes. The x- and y-axis correspond to the third and second PCs, respectively. In contrast to the results of panel b, the third PC failed to show separation of trisomic from euploid samples (6.9% of total variance). The ellipsoids represent three standard deviations beyond the centroid of each tissue group. Data points correspond to samples (red, Down syndrome; blue, euploid) within a group (cerebrum, diamond symbols on data points, and green ellipsoid; cerebellum, square symbols on data points and blue ellipsoid; astrocyte, triangle symbols on data points and red ellipsoid; heart, hexagon symbols on data points and orange ellipsoid).CC BY · PubMed Central
Figure 2 Dendrograms from hierarchical clustering. Dendrograms were based on (a) chromosome 21 genes and (b) non-chromosome 21 genes in the 25 samples, using Euclidean distance and average linkage. Branch lengths represent dissimilarity. Samples were of two types (TS21, red; euploid, dark blue) and four sources (astrocyte, green; cerebellum, light blue; cerebrum, gray; heart, brown).
Figure 2 Dendrograms from hierarchical clustering. Dendrograms were based on (a) chromosome 21 genes and (b) non-chromosome 21 genes in the 25 samples, using Euclidean distance and average linkage. Branch lengths represent dissimilarity. Samples were of two types (TS21, red; euploid, dark blue) and four sources (astrocyte, green; cerebellum, light blue; cerebrum, gray; heart, brown).CC BY · PubMed Central
Figure 3 Increased transcript levels of genes assigned to chromosome 21 in TS21 samples compared to controls. The plots show ratio (TS21/euploid) of mean expression values, calculated using data from samples in each tissue or cell type, for all 23 chromosomes. (X and Y chromosome data were pooled.) The expression values were obtained with Affymetrix MAS5 software. The error bars represent standard errors (obtained by performing 1,000 iterations of a bootstrap resampling of the tissues). (a) The ratio of TS21 to euploid mean expression values for each chromosome in fetal cerebrum samples. (b) The ratio of TS21 to euploid mean expression values in fetal cerebellum samples. (c) The ratio of TS21 to euploid mean expression values in cultured astrocyte cell lines derived from fetal cerebrum tissues. (d) The ratio of TS21 to euploid mean expression values in fetal heart samples. (e) The ratio of TS21 to euploid mean expression values using data from all the above tissue and cell types.
Figure 3 Increased transcript levels of genes assigned to chromosome 21 in TS21 samples compared to controls. The plots show ratio (TS21/euploid) of mean expression values, calculated using data from samples in each tissue or cell type, for all 23 chromosomes. (X and Y chromosome data were pooled.) The expression values were obtained with Affymetrix MAS5 software. The error bars represent standard errors (obtained by performing 1,000 iterations of a bootstrap resampling of the tissues). (a) The ratio of TS21 to euploid mean expression values for each chromosome in fetal cerebrum samples. (b) The ratio of TS21 to euploid mean expression values in fetal cerebellum samples. (c) The ratio of TS21 to euploid mean expression values in cultured astrocyte cell lines derived from fetal cerebrum tissues. (d) The ratio of TS21 to euploid mean expression values in fetal heart samples. (e) The ratio of TS21 to euploid mean expression values using data from all the above tissue and cell types.CC BY · PubMed Central
Figure 4 Histograms of p values. (a) Distribution of p values for chromosome 21 genes (253 probe sets represented on the microarray). The histogram contains 20 bins, at intervals of 0.05. The expected number of genes in each bin by chance alone is 253 × 0.05 = 12.65 (horizontal line). (b) Distribution of p values for non-chromosome 21 genes (20,008 probe sets). The expected number of genes having a p value < 0.05 by random chance is 20,008 × 0.05 = 1000.4 (horizontal line).
Figure 4 Histograms of p values. (a) Distribution of p values for chromosome 21 genes (253 probe sets represented on the microarray). The histogram contains 20 bins, at intervals of 0.05. The expected number of genes in each bin by chance alone is 253 × 0.05 = 12.65 (horizontal line). (b) Distribution of p values for non-chromosome 21 genes (20,008 probe sets). The expected number of genes having a p value < 0.05 by random chance is 20,008 × 0.05 = 1000.4 (horizontal line).CC BY · PubMed Central

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Research works printed but not linked: 1

  1. Lejeune J, Gautier M, Turpin R: Etudes des chromosomes somatique de neuf enfants mongoliens. Comptes Rendus Academie des Sciences Paris. 1959, 248: 1721-1722.

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Metadata

Authors
Mao, R., Wang, X., Spitznagel, E. L., Frelin, L. P., Ting, J. C., Ding, H., Kim, J.-W., Ruczinski, I., Downey, T. J., & Pevsner, J.
Affiliations
  • Johns Hopkins University (US)
  • Partek (United States) (US)
  • Washington University in St. Louis (US)
  • Kennedy Krieger Institute (US)
Corresponding author
Pevsner, Jonathan
ORCID
Venue
Genome Biology
Publisher
Springer Science and Business Media LLC
Published
2005-12-16
Volume
6
Issue
13
Pages
R107-R107
ISSN
  • 1465-6906 (ISSN-L)
  • 1474-760X
DOI
10.1186/gb-2005-6-13-r107
PMC
PMC1414106
OpenAlex
W2159929448
Cited by
166
References
58
Citations by year
2025: 5 · 2024: 2 · 2023: 4 · 2022: 7 · 2021: 10 · 2020: 5 · 2019: 8 · 2018: 7 · 2017: 9 · 2016: 4 · 2015: 2 · 2014: 8 · 2013: 11 · 2012: 15
FWCI
12.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Genome biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Johns Hopkins University
  • National Institutes of Health
  • Johns Hopkins Bloomberg School of Public Health
  • National Cancer Institute (CA074841, R29CA074841, R01CA074841)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD046598)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
Keywords
Down syndrome, gene expression dysregulation, transcriptome, fetal cerebellum, fetal heart, tissue-specific gene expression, intellectual disability, differentially expressed genes
MeSH terms
Astrocytes, Cell Line, Chromosomes, Human, Pair 21, Down Syndrome, Fetus, Heart, Humans, Myocardium, RNA, Messenger, Telencephalon, Transcription, Genetic, Reproducibility of Results, Cluster Analysis, Gene Expression Regulation, Developmental, Principal Component Analysis, Microarray Analysis

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