Date Published: January 26, 2017
Publisher: Public Library of Science
Author(s): Kejian Wang, Vikrant Vijay, James C. Fuscoe, Neena B. Haider.
Stably Expressed Genes (SEGs) whose expression varies within a narrow range may be involved in core cellular processes necessary for basic functions. To identify such genes, we re-analyzed existing RNA-Seq gene expression profiles across 11 organs at 4 developmental stages (from immature to old age) in both sexes of F344 rats (n = 4/group; 320 samples). Expression changes (calculated as the maximum expression / minimum expression for each gene) of >19000 genes across organs, ages, and sexes ranged from 2.35 to >109-fold, with a median of 165-fold. The expression of 278 SEGs was found to vary ≤4-fold and these genes were significantly involved in protein catabolism (proteasome and ubiquitination), RNA transport, protein processing, and the spliceosome. Such stability of expression was further validated in human samples where the expression variability of the homologous human SEGs was significantly lower than that of other genes in the human genome. It was also found that the homologous human SEGs were generally less subject to non-synonymous mutation than other genes, as would be expected of stably expressed genes. We also found that knockout of SEG homologs in mouse models was more likely to cause complete preweaning lethality than non-SEG homologs, corroborating the fundamental roles played by SEGs in biological development. Such stably expressed genes and pathways across life-stages suggest that tight control of these processes is important in basic cellular functions and that perturbation by endogenous (e.g., genetics) or exogenous agents (e.g., drugs, environmental factors) may cause serious adverse effects.
The development of genome-wide transcriptional profiling techniques has enabled measurement of the expression of tens of thousands of genes in parallel . A consensus has formed that the status of a cell or an organ is, at least partially, a function of gene expression levels . Frequently, investigations using transcriptomics data identify the genes whose expression levels differ between distinct biological conditions; for example, normal verses diseased tissues , or perturbed verses unperturbed samples . Genes that are mostly responsible for the difference between the biological states are defined as differentially expressed genes (DEGs), which aid in the development of biomarkers for clinical diagnosis  and the understanding of diverse biological mechanisms of diseases [6, 7].
In the present study, we identified genes whose expression varied within a relatively narrow range across the life span, and between sexes and organs in F344 rats. The proteins encoded by these SEGs were found to play important roles in basic cellular functions, including protein catabolism (proteasome and ubiquitination), RNA transport, protein processing, and the spliceosome, and suggested stable expression of these genes is fundamental to good health. Several lines of evidence support the validity of these findings. First, the low expression variability of these genes was conserved across species. Examination of the expression of the human homologs of the rat SEGs in a database of tissues derived from humans (GTEx) showed that these genes exhibited much less expression variability across tissue, age and sex than other genes (p< 2.5 x 10−104). Second, we hypothesized that the transcriptomic stability of the SEGs played a pivotal role in normal physiological function and that dysregulation would result in disease or lethality. Examination of the effect of knocking out individual SEGs in mouse models developed in the International Mouse Phenotyping Consortium showed a lethal phenotype at the prenatal stage for a high proportion of SEGs. Of the 16 strains with knock-out of the mouse homolog of a rat SEG, 15 resulted in complete preweaning lethality (>93%); knocking out the mouse homologs of rat non-SEGs (1341 genes) resulted in complete preweaning lethality only 31% of the time, supporting the importance of these SEGs in development (p< 3.8 x 10−7). Third, we hypothesized that SEGs would be under evolutionary pressure to maintain stable expression and this would be reflected in the accumulation of fewer mutations in these genes. Recently, a human gene damage index (GDI) summarizing the non-synonymous mutational load of each protein-coding gene in the general human population was developed . Examination of this database showed that the human homologs of the rat SEGs were less frequently mutated in healthy populations and exhibited lower GDI (p = 1.92×10−5). Thus, from multiple independent perspectives, stably expressed genes encoding proteins involved in protein catabolism, RNA transport, protein processing, and the spliceosome, appear to be of fundamental importance. Source: http://doi.org/10.1371/journal.pone.0170813