title: Bimodal distribution of RNA expression levels in human skeletal muscle tissue.
abstract: BACKGROUND
  Many human diseases and phenotypes are related to RNA expression, levels of which are influenced by a wide spectrum of genetic and exposure-related factors. In a large genome-wide study of muscle tissue expression, we found that some genes exhibited a bimodal distribution of RNA expression, in contrast to what is usually assumed in studies of a single healthy tissue. As bimodality has classically been considered a hallmark of genetic control, we assessed the genome-wide prevalence, cause, and association of this phenomenon with diabetes-related phenotypes in skeletal muscle tissue from 225 healthy Pima Indians using exon array expression chips.
  
  
  RESULTS
  Two independent batches of microarrays were used for bimodal assessment and comparison. Of the 17,881 genes analyzed, eight (GSTM1, HLA-DRB1, ERAP2, HLA-DRB5, MAOA, ACTN3, NR4A2, and THNSL2) were found to have bimodal expression replicated in the separate batch groups, while 24 other genes had evidence of bimodality in only one group. Some bimodally expressed genes had modest associations with pre-diabetic phenotypes, of note ACTN3 with insulin resistance. Most of the other bimodal genes have been reported to be involved with various other diseases and characteristics. Association of expression with cis genetic variation in a subset of 149 individuals found all but one of the confirmed bimodal genes and nearly half of all potential ones to be highly significant expression quantitative trait loci (eQTL). The rare prevalence of these bimodally expressed genes found after controlling for batch effects was much lower than the prevalence reported in other studies. Additional validation in data from separate muscle expression studies confirmed the low prevalence of bimodality we observed.
  
  
  CONCLUSIONS
  We conclude that the prevalence of bimodal gene expression is quite rare in healthy muscle tissue (<0.2%), and is much lower than limited reports from other studies. The major cause of these clearly bimodal expression patterns in homogeneous tissue appears to be cis-polymorphisms, indicating that such bimodal genes are, for the most part, eQTL. The high frequency of disease associations reported with these genes gives hope that this unique feature may identify or actually be an underlying factor responsible for disease development.
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 1550 E, Indian School Rd, Phoenix, AZ 85014, USA. masonclint@niddk.nih.gov
authors.forename: Clinton C
authors.initials: CC
authors.lastname: Mason
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hanson
authors.forename: Vicky
authors.initials: V
authors.lastname: Ossowski
authors.forename: Li
authors.initials: L
authors.lastname: Bian
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Baier
authors.forename: Jonathan
authors.initials: J
authors.lastname: Krakoff
authors.forename: Clifton
authors.initials: C
authors.lastname: Bogardus
mesh_terms: D000185:Actinin / Q000235:genetics; D000626:Aminopeptidases / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D059847:HLA-DRB5 Chains; D006801:Humans; D066298:In Vitro Techniques; D008995:Monoamine Oxidase / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics; D010641:Phenotype; D040641:Quantitative Trait Loci / Q000235:genetics; D012335:RNA, Ribosomal / Q000235:genetics
chemical_list: D000185:Actinin; D000626:Aminopeptidases; D005982:Glutathione Transferase; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D059847:HLA-DRB5 Chains; D008995:Monoamine Oxidase; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012335:RNA, Ribosomal; C118456:ACTN3 protein, human; C539882:NR4A2 protein, human; C503944:ERAP2 protein, human