The choice of the filtering method in microarrays affects the inference regarding dosage compensation of the active X-chromosome
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The choice of the filtering method in microarrays affects the inference regarding dosage compensation of the active X-chromosome. / Castagné, Raphaële; Rotival, Maxime; Zeller, Tanja; Wild, Philipp S; Truong, Vinh; Trégouët, David-Alexandre; Munzel, Thomas; Ziegler, Andreas; Cambien, François; Blankenberg, Stefan; Tiret, Laurence.
in: PLOS ONE, Jahrgang 6, Nr. 9, 2011, S. e23956.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - The choice of the filtering method in microarrays affects the inference regarding dosage compensation of the active X-chromosome
AU - Castagné, Raphaële
AU - Rotival, Maxime
AU - Zeller, Tanja
AU - Wild, Philipp S
AU - Truong, Vinh
AU - Trégouët, David-Alexandre
AU - Munzel, Thomas
AU - Ziegler, Andreas
AU - Cambien, François
AU - Blankenberg, Stefan
AU - Tiret, Laurence
PY - 2011
Y1 - 2011
N2 - BACKGROUND: The hypothesis of dosage compensation of genes of the X chromosome, supported by previous microarray studies, was recently challenged by RNA-sequencing data. It was suggested that microarray studies were biased toward an over-estimation of X-linked expression levels as a consequence of the filtering of genes below the detection threshold of microarrays.METHODOLOGY/PRINCIPAL FINDINGS: To investigate this hypothesis, we used microarray expression data from circulating monocytes in 1,467 individuals. In total, 25,349 and 1,156 probes were unambiguously assigned to autosomes and the X chromosome, respectively. Globally, there was a clear shift of X-linked expressions toward lower levels than autosomes. We compared the ratio of expression levels of X-linked to autosomal transcripts (X∶AA) using two different filtering methods: 1. gene expressions were filtered out using a detection threshold irrespective of gene chromosomal location (the standard method in microarrays); 2. equal proportions of genes were filtered out separately on the X and on autosomes. For a wide range of filtering proportions, the X∶AA ratio estimated with the first method was not significantly different from 1, the value expected if dosage compensation was achieved, whereas it was significantly lower than 1 with the second method, leading to the rejection of the hypothesis of dosage compensation. We further showed in simulated data that the choice of the most appropriate method was dependent on biological assumptions regarding the proportion of actively expressed genes on the X chromosome comparative to the autosomes and the extent of dosage compensation.CONCLUSION/SIGNIFICANCE: This study shows that the method used for filtering out lowly expressed genes in microarrays may have a major impact according to the hypothesis investigated. The hypothesis of dosage compensation of X-linked genes cannot be firmly accepted or rejected using microarray-based data.
AB - BACKGROUND: The hypothesis of dosage compensation of genes of the X chromosome, supported by previous microarray studies, was recently challenged by RNA-sequencing data. It was suggested that microarray studies were biased toward an over-estimation of X-linked expression levels as a consequence of the filtering of genes below the detection threshold of microarrays.METHODOLOGY/PRINCIPAL FINDINGS: To investigate this hypothesis, we used microarray expression data from circulating monocytes in 1,467 individuals. In total, 25,349 and 1,156 probes were unambiguously assigned to autosomes and the X chromosome, respectively. Globally, there was a clear shift of X-linked expressions toward lower levels than autosomes. We compared the ratio of expression levels of X-linked to autosomal transcripts (X∶AA) using two different filtering methods: 1. gene expressions were filtered out using a detection threshold irrespective of gene chromosomal location (the standard method in microarrays); 2. equal proportions of genes were filtered out separately on the X and on autosomes. For a wide range of filtering proportions, the X∶AA ratio estimated with the first method was not significantly different from 1, the value expected if dosage compensation was achieved, whereas it was significantly lower than 1 with the second method, leading to the rejection of the hypothesis of dosage compensation. We further showed in simulated data that the choice of the most appropriate method was dependent on biological assumptions regarding the proportion of actively expressed genes on the X chromosome comparative to the autosomes and the extent of dosage compensation.CONCLUSION/SIGNIFICANCE: This study shows that the method used for filtering out lowly expressed genes in microarrays may have a major impact according to the hypothesis investigated. The hypothesis of dosage compensation of X-linked genes cannot be firmly accepted or rejected using microarray-based data.
KW - Animals
KW - Chromosomes, Human, X/genetics
KW - Dosage Compensation, Genetic/genetics
KW - Female
KW - Gene Expression Profiling
KW - Genes, X-Linked/genetics
KW - Genomic Imprinting
KW - HEK293 Cells
KW - Humans
KW - Male
KW - Mice
KW - Models, Genetic
KW - Monocytes/metabolism
KW - Oligonucleotide Array Sequence Analysis/methods
KW - RNA, Messenger/genetics
U2 - 10.1371/journal.pone.0023956
DO - 10.1371/journal.pone.0023956
M3 - SCORING: Journal article
C2 - 21912656
VL - 6
SP - e23956
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 9
ER -