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Functionalities of expressed messenger RNAs revealed from mutant phenotypes

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Total messenger RNAs mRNAs that are produced from a given gene under a certain set of conditions include both functional and nonfunctional transcripts. The high prevalence of nonfunctional mRNAs that have been detected in cells has raised questions regarding the functional implications of mRNA expression patterns and divergences. Phenotypes that result from the mutagenesis of protein‐coding genes have provided the most straightforward descriptions of gene functions, and such data obtained from model organisms have facilitated investigations of the functionalities of expressed mRNAs. Mutant phenotype data from mouse tissues have revealed various attributes of functional mRNAs, including tissue‐specificity, strength of expression, and evolutionary conservation. In addition, the role that mRNA expression evolution plays in driving morphological evolution has been revealed from studies designed to exploit morphological and physiological phenotypes of mouse mutants. Investigations into yeast essential genes (defined by an absence of colony growth after gene deletion) have further described gene regulatory strategies that reduce protein expression noise by mediating the rates of transcription and translation. In addition to the functional significance of expressed mRNAs as described in the abovementioned findings, the functionalities of other type of RNAs (i.e., noncoding RNAs) remain to be characterized with systematic mutations and phenotyping of the DNA regions that encode these RNA molecules. WIREs RNA 2016, 7:416–427. doi: 10.1002/wrna.1329 This article is categorized under: RNA Evolution and Genomics > Computational Analyses of RNA RNA in Disease and Development > RNA in Development
Proportion of nonfunctional (shown in gray) versus functional (shown in blue) expressed mRNAs for conditions I–VIII (a) and for hypothetical genes, X, Y, and Z (b). The designations, low, medium, and high, were used to compare the functionalities of the expressed mRNAs among the three conditions that are connected by a curve line in (a) and among the three genes, X, Y, and Z, in (b). The functionalities of the expressed mRNAs at the gene level are based on a summation of the functional mRNA expression levels divided by the total mRNA expression levels for conditions I–VIII, and among genes X, Y, and Z, respectively. Regarding the latter, gene X and gene Y have the same level of total expressed mRNAs across conditions I–VIII, although the proportion of functional and nonfunctional mRNAs vary across the conditions. Alternatively, gene Y and gene Z have the same level of functional expressed mRNAs, while the condition‐specific totals for the expressed mRNAs differ.
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(a) Reduced protein expression noise can be achieved by maximizing transcription and minimizing translation per mRNA. The left and right regulatory schemes produce the same amount of proteins, but are associated with low versus high levels of protein noise, respectively. (b) The regulatory strategy shown in (a, left) to reduce protein expression noise is often utilized by yeast essential genes, which are defined as genes with a knockout phenotype characterized by a zero rate of colony growth (fitness = 0, shown in red), compared with nonessential genes (shown in gray).
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Morphological abnormalities (blue) and physiological abnormalities (red) that were observed for the mutated mouse genes were used to define the morphogenes and physiogenes, respectively. In (a), only 8 out of the 192 phenotypic terms used for gene classification are shown as examples. Each term contains many descendent terms, and the numbers listed to the right of the triangles are the numbers of descendent terms. (b) The proportion of morphogenes (n = 821) and physiogenes (n = 912) that were identified among the total number of genes examined are represented in a Venn diagram.
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The phenotypic profile (a) and the expression profile (b) for the Acacb gene across 47 mouse tissues. In (a), the colored terms list the knockout phenotypes of the Acacb gene as annotated by Mouse Genome Informatics (MGI). Three annotated term groups for the tissues indicated are listed with their associated phenotypic terms (only terms associated with higher levels of the colored terms are specifically shown). In (b), mRNA hybridization signals were measured based on the average difference (AD) values that were obtained from Affymetrix oligonucleotide microarrays; an AD value >200 indicates detectable mRNA expression.
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An example of the phenotype annotations that are used as unique identifiers (adopted for mouse) (left) or composite terms (adopted for fruit fly) (right) to characterize embryonic lethality (mouse, death before organogenesis; fly, death before hatching) (a) or reduced male fertility (reduced ability of male to produce live offspring) phenotypes (b). Only a small fraction of the phenotypic terms that are relevant are shown. The sizes of the triangles are proportional to the numbers of descendant terms (indicated to the right of the triangle).
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The mRNA expression profile and knockout phenotypes of the mouse Mov10l1 gene. Using Affymetrix oligonucleotide microarrays, mRNA hybridization signals were measured as average difference (AD) values; an AD value >200 indicates detectable mRNA expression in the tissues. Only tissues with both mRNA expression data and phenotypic data were included. In the two tissues with an AD value >200 (heart and testis), only the testis exhibited phenotypic abnormalities (as described in the blue box) following the targeted deletion of Mov10l1.
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RNA in Disease and Development > RNA in Development
RNA Evolution and Genomics > Computational Analyses of RNA

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