title: Unraveling the association between mRNA expressions and mutant phenotypes in a genome-wide assessment of mice.
abstract: High-throughput gene expression profiling has revealed substantial leaky and extraneous transcription of eukaryotic genes, challenging the perceptions that transcription is strictly regulated and that changes in transcription have phenotypic consequences. To assess the functional implications of mRNA transcription directly, we analyzed mRNA expression data derived from microarrays, RNA-sequencing, and in situ hybridization, together with phenotype data of mouse mutants as a proxy of gene function at the tissue level. The results indicated that despite the presence of widespread ectopic transcription, mRNA expression and mutant phenotypes of mammalian genes or tissues remain associated. The expression-phenotype association at the gene level was particularly strong for tissue-specific genes, and the association could be underestimated due to data insufficiency and incomprehensive phenotyping of mouse mutants; the strength of expression-phenotype association at the tissue level depended on tissue functions. Mutations on genes expressed at higher levels or expressed at earlier embryonic stages more often result in abnormal phenotypes in the tissues where they are expressed. The mRNA expression profiles that have stronger associations with their phenotype profiles tend to be more evolutionarily conserved, indicating that the evolution of transcriptome and the evolution of phenome are coupled. Therefore, mutations resulting in phenotypic aberrations in expressed tissues are more likely to occur in highly transcribed genes, tissue-specific genes, genes expressed during early embryonic stages, or genes with evolutionarily conserved mRNA expression profiles.
authors.affiliation: Division of Biostatistics & Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Miaoli County 350, Taiwan, Republic of China liaoby@nhri.org.tw.
authors.forename: Ben-Yang
authors.initials: BY
authors.lastname: Liao
authors.affiliation: Division of Biostatistics & Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Miaoli County 350, Taiwan, Republic of China.
authors.forename: Meng-Pin
authors.initials: MP
authors.lastname: Weng
mesh_terms: D000465:Algorithms; D000818:Animals; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D063990:Gene Ontology; D016678:Genome / Q000235:genetics*; D051379:Mice; D008957:Models, Genetic; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity / Q000235:genetics; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D012641:Selection, Genetic
chemical_list: D012333:RNA, Messenger
keywords: developmental stages; ectopic expression; mRNA abundance; molecular evolution; tissue specificity
references.citation: PLoS Biol. 2011 Jul;9(7):e1000625; discussion e1001102
references.pmid: 21765801
references.citation: Nat Rev Genet. 2009 Jan;10(1):57-63
references.pmid: 19015660
references.citation: J Clin Invest. 1999 Feb;103(4):497-505
references.pmid: 10021458
references.citation: Genetica. 2007 Oct;131(2):151-6
references.pmid: 17160620
references.citation: Mol Biol Evol. 2006 Mar;23(3):530-40
references.pmid: 16280543
references.citation: Nat Rev Genet. 2007 Mar;8(3):206-16
references.pmid: 17304246
references.citation: J Biol. 2002;1(1):5
references.pmid: 12144710
references.citation: Bioessays. 2005 Jun;27(6):592-601
references.pmid: 15892118
references.citation: Nucleic Acids Res. 2010 Jun;38(10):e115
references.pmid: 20164092
references.citation: Nature. 2014 Mar 27;507(7493):462-70
references.pmid: 24670764
references.citation: Circulation. 2007 Jun 12;115(23):3015-38
references.pmid: 17519398
references.citation: Bioinformatics. 2005 Mar15;21(6):832-4
references.pmid: 15531608
references.citation: Mol Syst Biol. 2011;7:497
references.pmid: 21654674
references.citation: Science. 1984 Apr 20;224(4646):256-62
references.pmid: 6538699
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10662-7
references.pmid: 8855236
references.citation: Science. 1975 Apr 11;188(4184):107-16
references.pmid: 1090005
references.citation: Nature. 2011 Jun 16;474(7351):380-4
references.pmid: 21614001
references.citation: Hum Mol Genet. 2013 Dec 15;22(24):5001-14
references.pmid: 23904455
references.citation: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D637-41
references.pmid: 16381949
references.citation: Mol Biol Evol. 2008 Aug;25(8):1555-65
references.pmid: 18440951
references.citation: Nucleic Acids Res. 2007 Jan;35(Database issue):D610-7
references.pmid: 17148474
references.citation: Genes Dev. 2002 Jan 1;16(1):6-21
references.pmid: 11782440
references.citation: Cell. 2002 May 3;109(3):267-70
references.pmid: 12015975
references.citation: Nature. 2003 Apr 10;422(6932):633-7
references.pmid: 12687005
references.citation: Trends Genet. 2007 Aug;23(8):378-81
references.pmid: 17559966
references.citation: PLoS Biol. 2004 May;2(5):E132
references.pmid: 15138501
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6062-7
references.pmid: 15075390
references.citation: Nature. 2011 Oct 20;478(7369):343-8
references.pmid: 22012392
references.citation: Mamm Genome. 2012 Oct;23(9-10):653-68
references.pmid: 22961259
references.citation: Nat Genet. 2005 May;37(5):544-8
references.pmid: 15852004
references.citation: Nat Rev Genet. 2008 Oct;9(10):803-10
references.pmid: 18781157
references.citation: PLoS Comput Biol. 2006 May;2(5):e48
references.pmid: 16733546
references.citation: PLoS Biol. 2009 Mar 3;7(3):e48
references.pmid: 19260763
references.citation: Bioinformatics. 2010 Sep 1;26(17):2212-3
references.pmid: 20605928
references.citation: Trends Genet. 2005 Feb;21(2):93-102
references.pmid: 15661355
references.citation: Mol Biol Evol. 2006 Jun;23(6):1119-28
references.pmid: 16520335
references.citation: Int J Dev Biol. 2000 Oct;44(7):769-76
references.pmid: 11128570
references.citation: Database (Oxford). 2011;2011:bar029
references.pmid: 21930504
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 8;108(10):4258-63
references.pmid: 21368118
references.citation: J Biomed Semantics. 2013 Aug 26;4(1):15
references.pmid: 23972281
references.citation: Mol Cell Biol. 2002 Jun;22(12):4158-66
references.pmid: 12024029
references.citation: Gene. 2005 Jan 17;345(1):119-26
references.pmid: 15716085
references.citation: BMC Syst Biol. 2012;6 Suppl 2:S1
references.pmid: 23281795