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Analyses of allele-specific gene expression in highly divergent mouse crosses identifies pervasive allelic imbalance.

ABSTRACT: Complex human traits are influenced by variation in regulatory DNA through mechanisms that are not fully understood. Because regulatory elements are conserved between humans and mice, a thorough annotation of cis regulatory variants in mice could aid in further characterizing these mechanisms. Here we provide a detailed portrait of mouse gene expression across multiple tissues in a three-way diallel. Greater than 80% of mouse genes have cis regulatory variation. Effects from these variants influence complex traits and usually extend to the human ortholog. Further, we estimate that at least one in every thousand SNPs creates a cis regulatory effect. We also observe two types of parent-of-origin effects, including classical imprinting and a new global allelic imbalance in expression favoring the paternal allele. We conclude that, as with humans, pervasive regulatory variation influences complex genetic traits in mice and provide a new resource toward understanding the genetic control of transcription in mammals.

SUBMITTER: Crowley JJ

PROVIDER: S-EPMC4380817 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Analyses of allele-specific gene expression in highly divergent mouse crosses identifies pervasive allelic imbalance.

Crowley James J JJ Zhabotynsky Vasyl V Sun Wei W Huang Shunping S Pakatci Isa Kemal IK Kim Yunjung Y Wang Jeremy R JR Morgan Andrew P AP Calaway John D JD Aylor David L DL Yun Zaining Z Bell Timothy A TA Buus Ryan J RJ Calaway Mark E ME Didion John P JP Gooch Terry J TJ Hansen Stephanie D SD Robinson Nashiya N NN Shaw Ginger D GD Spence Jason S JS Quackenbush Corey R CR Barrick Cordelia J CJ Nonneman Randal J RJ Kim Kyungsu K Xenakis James J Xie Yuying Y Valdar William W Lenarcic Alan B AB Wang Wei W Welsh Catherine E CE Fu Chen-Ping CP Zhang Zhaojun Z Holt James J Guo Zhishan Z Threadgill David W DW Tarantino Lisa M LM Miller Darla R DR Zou Fei F McMillan Leonard L Sullivan Patrick F PF Pardo-Manuel de Villena Fernando F

Nature genetics 20150302 4

Complex human traits are influenced by variation in regulatory DNA through mechanisms that are not fully understood. Because regulatory elements are conserved between humans and mice, a thorough annotation of cis regulatory variants in mice could aid in further characterizing these mechanisms. Here we provide a detailed portrait of mouse gene expression across multiple tissues in a three-way diallel. Greater than 80% of mouse genes have cis regulatory variation. Effects from these variants influ ...[more]

PMID: 25730764

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Project description:Allelic imbalance of thymidylate synthase (TYMS) is attributed to polymorphisms in the 5'- and 3'-untranslated region (UTR). These polymorphisms have been related to the risk of suffering different cancers, for example leukemia, breast or gastric cancer, and response to different drugs, among which are methotrexate glutamates, stavudine, and specifically 5-fluorouracil (5-FU), as TYMS is its direct target. A vast literature has been published in relation to 5-FU, even suggesting the sole use of these polymorphisms to effectively manage 5-FU dosage. Estimates of the extent to which these polymorphisms influence in TYMS expression have in the past been based on functional analysis by luciferase assays and quantification of TYMS mRNA, but both these studies, as the association studies with cancer risk or with toxicity or response to 5-FU, are very contradictory. Regarding functional assays, the artificial genetic environment created in luciferase assay and the problems derived from quantitative polymerase chain reactions (qPCRs), for example the use of a reference gene, may have distorted the results. To avoid these sources of interference, we have analyzed the allelic imbalance of TYMS by allelic-specific analysis in peripheral blood mononuclear cells (PBMCs) from patients.Allelic imbalance in PBMCs, taken from 40 patients with suspected myeloproliferative haematological diseases, was determined by fluorescent fragment analysis (for the 3'-UTR polymorphism), Sanger sequencing and allelic-specific qPCR in multiplex (for the 5'-UTR polymorphisms).For neither the 3'- nor the 5'-UTR polymorphisms did the observed allelic imbalance exceed 1.5 fold. None of the TYMS polymorphisms is statistically associated with allelic imbalance.The results acquired allow us to deny the previously established assertion of an influence of 2 to 4 fold of the rs45445694 and rs2853542 polymorphisms in the expression of TYMS and narrow its allelic imbalance to 1.5 fold, in our population. These data circumscribe the influence of these polymorphisms in the clinical outcome of 5-FU and question their use for establishing 5-FU dosage, above all when additional genetic factors are not considered.

Dataset Information

Analyses of allele-specific gene expression in highly divergent mouse crosses identifies pervasive allelic imbalance.

Publications

Analyses of allele-specific gene expression in highly divergent mouse crosses identifies pervasive allelic imbalance.

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