title: The abundance of cis-acting loci leading to differential allele expression in F1 mice and their relationship to loci harboring genes affecting complex traits.
abstract: Genome-wide surveys have detected cis-acting quantitative trait loci altering levels of RNA transcripts (RNA-eQTLs) by associating SNV alleles to transcript levels. However, the sensitivity and specificity of detection of cis- expression quantitative trait loci (eQTLs) by genetic approaches, reliant as it is on measurements of transcript levels in recombinant inbred strains or offspring from arranged crosses, is unknown, as is their relationship to QTL's for complex phenotypes.
  
  
  
  We used transcriptome-wide differential allele expression (DAE) to detect cis-eQTLs in forebrain and kidney from reciprocal crosses between three mouse inbred strains, 129S1/SvlmJ, DBA/2J, and CAST/EiJ and C57BL/6 J. Two of these crosses were previously characterized for cis-eQTLs and QTLs for various complex phenotypes by genetic analysis of recombinant inbred (RI) strains. 5.4 %, 1.9 % and 1.5 % of genes assayed in forebrain of B6/129SF1, B6/DBAF1, and B6/CASTF1 mice, respectively, showed differential allelic expression, indicative of cis-acting alleles at these genes. Moreover, the majority of DAE QTLs were observed to be tissue-specific with only a small fraction showing cis-effects in both tissues. Comparing DAE QTLs in F1 mice to cis-eQTLs previously mapped in RI strains we observed that many of the cis-eQTLs were not confirmed by DAE. Additionally several novel DAE-QTLs not identified as cis-eQTLs were identified suggesting that there are differences in sensitivity and specificity for QTL detection between the two methodologies. Strain specific DAE QTLs in B6/DBAF1 mice were located in excess at candidate genes for alcohol use disorders, seizures, and angiogenesis previously implicated by genetic linkage in C57BL/6J × DBA/2JF2 mice or BXD RI strains.
  
  
  
  Via a survey for differential allele expression in F1 mice, a substantial proportion of genes were found to have alleles altering expression in cis-acting fashion. Comparing forebrain and kidney, many or most of these alleles were tissue-specific in action. The identification of strain specific DAE QTLs, can assist in assessment of candidate genes located within the large intervals associated with trait QTLs.
authors: Laboratory of Neurogenetics, National institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20852, USA.
authors: Seungeun
authors: S
authors: Yeo
authors: Laboratory of Neurogenetics, National institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20852, USA.
authors: Colin A
authors: CA
authors: Hodgkinson
authors: Laboratory of Neurogenetics, National institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20852, USA.
authors: Zhifeng
authors: Z
authors: Zhou
authors: Laboratory of Epidemiology and Biometry, National institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20852, USA.
authors: Jeesun
authors: J
authors: Jung
authors: Laboratory of Neurogenetics, National institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20852, USA.
authors: Ming
authors: M
authors: Leung
authors: Laboratory of Neurogenetics, National institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20852, USA.
authors: Qiaoping
authors: Q
authors: Yuan
authors: Laboratory of Neurogenetics, National institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20852, USA. davidgoldman@mail.nih.gov.
authors: David
authors: D
authors: Goldman
mesh_terms: D000437:Alcoholism / Q000235:genetics / Q000473:pathology; D000483:Alleles; D000818:Animals; D003433:Crosses, Genetic; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D040582:Inheritance Patterns; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D009928:Organ Specificity; D010641:Phenotype; D016548:Prosencephalon / Q000378:metabolism / Q000473:pathology; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D012640:Seizures / Q000235:genetics / Q000473:pathology; D059467:Transcriptome
keywords: Differential allelic expression; Quantitative trait loci; RNA-Seq; cis-acting loci