Mammalian mRNA splice-isoform selection is tightly controlled

Post-transcriptional RNA processing is an important regulatory control mechanism for determining the phenotype of eukaryotic cells. The processing of a transcribed RNA species into alternative splice isoforms yields products that can perform different functions. Each type of cell in a multi-cellular organism is presumed to actively control the relative quantities of alternative splice isoforms. In this study, the alternatively-spliced isoforms of five mRNA transcription units were examined by quantitative reverse transcription-PCR amplification. We show that inter-individual variation in splice-isoform selection is very highly constrained, when measured in a large population of genetically diverse mice (i.e., full siblings; N = 150). Remarkably, splice-isoform ratios are among the most invariant phenotypes measured in this population, and are confirmed in a second, genetically-distinct population. In addition, the patterns of splice-isoform selection show tissue-specific and age-related changes. We propose that splice-isoform selection is exceptionally robust to genetic and environmental variability, and may provide a control point for cellular homeostasis. As a consequence, splice-isoform ratios may be useful as a practical quantitative measure of the physiological status of cells and tissues.

Key Words: alternative splicing, homeostasis, isoforms, mouse, robustness

Online ISS 1091-6490
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