Abstract
Down syndrome (DS) is mostly caused by a trisomy of the entire Chromosome 21 (Trisomy 21, T21). Here, we use SWATH mass spectrometry to quantify protein abundance and protein turnover in fibroblasts from a monozygotic twin pair discordant for T21, and to profile protein expression in 11 unrelated DS individuals and matched controls. The integration of the steady-state and turnover proteomic data indicates that protein-specific degradation of members of stoichiometric complexes is a major determinant of T21 gene dosage outcome, both within and between individuals. This effect is not apparent from genomic and transcriptomic data. The data also reveal that T21 results in extensive proteome remodeling, affecting proteins encoded by all chromosomes. Finally, we find broad, organelle-specific post-transcriptional effects such as significant downregulation of the mitochondrial proteome contributing to T21 hallmarks. Overall, we provide a valuable proteomic resource to understand the origin of DS phenotypic manifestations.
Highlights
Down syndrome (DS) is mostly caused by a trisomy of the entire Chromosome 21 (Trisomy 21, T21)
Since DS is the prototype of a chromosome gain copy number variations (CNVs), we study the proteomic effects of T21
To accurately quantify the proteomic changes in DS, we used SWATHMS18 to analyze the proteome of fetal skin primary fibroblasts derived from 11 DS and 11 unrelated, sex and age-matched normal control (N) individuals[4], each with two experimental replicates
Summary
Down syndrome (DS) is mostly caused by a trisomy of the entire Chromosome 21 (Trisomy 21, T21). The integration of the steadystate and turnover proteomic data indicates that protein-specific degradation of members of stoichiometric complexes is a major determinant of T21 gene dosage outcome, both within and between individuals. This effect is not apparent from genomic and transcriptomic data. A simple working hypothesis suggests that human Chr[21] genes display altered expression in individuals with T21 due to genome dosage imbalance. A review of recent work integrating genomic, transcriptomic, and proteomic data has revealed that the effect of copy number variations (CNVs) on protein levels is much more complex than previously anticipated[9]. This unique design of our study allows us to compare the proteomic impact of T21 in a genetically identical background to the impact observed in genetically distinct individuals
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