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

Crowley JJ, Zhabotynsky V, Sun W, Huang S, Pakatci IK, Kim Y, Wang JR, Morgan AP, Calaway JD, Aylor DL, Yun Z, Bell TA, Buus RJ, Calaway ME, Didion JP, Gooch TJ, Hansen SD, Robinson NN, Shaw GD, Spence JS, Quackenbush CR, Barrick CJ, Nonneman RJ, Kim K, Xenakis J, Xie Y, Valdar W, Lenarcic AB, Wang W, Welsh CE, Fu CP, Zhang Z, Holt J, Guo Z, Threadgill DW, Tarantino LM, Miller DR, Zou F, McMillan L, Sullivan PF, Pardo-Manuel de Villena F - Nat. Genet. (2015)

Bottom Line: Complex human traits are influenced by variation in regulatory DNA through mechanisms that are not fully understood.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

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.

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Related in: MedlinePlus

Principal components of brain RNAseq and microarray expression levels across four tissues. Each point represents one animal with shape indicating sex (circle = female, square = male) and color indicating genotype. For the F1 animals, the outer color indicates maternal strain and the inner color paternal strain. (a) PC1 versus PC2 of the brain RNAseq total read counts for all autosomal genes. The three inbred strains form a near-perfect triangle with the F1 samples located between their corresponding parental strains. PC1 and PC2 account for 31% of the variance in TReC, indicating that genetic background is the overwhelming driver of gene expression difference, greatly exceeding the effects of parent-of-origin and sex. (b) PC1 versus PC2 of microarray expression values for all autosomal genes across four tissues. The pattern seen in the brain extends to multiple diverse tissues.
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Figure 2: Principal components of brain RNAseq and microarray expression levels across four tissues. Each point represents one animal with shape indicating sex (circle = female, square = male) and color indicating genotype. For the F1 animals, the outer color indicates maternal strain and the inner color paternal strain. (a) PC1 versus PC2 of the brain RNAseq total read counts for all autosomal genes. The three inbred strains form a near-perfect triangle with the F1 samples located between their corresponding parental strains. PC1 and PC2 account for 31% of the variance in TReC, indicating that genetic background is the overwhelming driver of gene expression difference, greatly exceeding the effects of parent-of-origin and sex. (b) PC1 versus PC2 of microarray expression values for all autosomal genes across four tissues. The pattern seen in the brain extends to multiple diverse tissues.

Mentions: Within each tissue, the overwhelming driver of differential gene expression was strain; this greatly exceeded the effects of parent-of-origin and sex (Fig. 2). For RNAseq, the first two principal components (PCs) accounted for ~30% of the total variation in autosomal total read count (TReC). The remaining top 10 PCs were also strongly determined by strain and, to a far lesser extent, parent-of-origin and sex, with no notable effects of the barcodes used for multiplexing (Supplementary Table 3).


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

Crowley JJ, Zhabotynsky V, Sun W, Huang S, Pakatci IK, Kim Y, Wang JR, Morgan AP, Calaway JD, Aylor DL, Yun Z, Bell TA, Buus RJ, Calaway ME, Didion JP, Gooch TJ, Hansen SD, Robinson NN, Shaw GD, Spence JS, Quackenbush CR, Barrick CJ, Nonneman RJ, Kim K, Xenakis J, Xie Y, Valdar W, Lenarcic AB, Wang W, Welsh CE, Fu CP, Zhang Z, Holt J, Guo Z, Threadgill DW, Tarantino LM, Miller DR, Zou F, McMillan L, Sullivan PF, Pardo-Manuel de Villena F - Nat. Genet. (2015)

Principal components of brain RNAseq and microarray expression levels across four tissues. Each point represents one animal with shape indicating sex (circle = female, square = male) and color indicating genotype. For the F1 animals, the outer color indicates maternal strain and the inner color paternal strain. (a) PC1 versus PC2 of the brain RNAseq total read counts for all autosomal genes. The three inbred strains form a near-perfect triangle with the F1 samples located between their corresponding parental strains. PC1 and PC2 account for 31% of the variance in TReC, indicating that genetic background is the overwhelming driver of gene expression difference, greatly exceeding the effects of parent-of-origin and sex. (b) PC1 versus PC2 of microarray expression values for all autosomal genes across four tissues. The pattern seen in the brain extends to multiple diverse tissues.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4380817&req=5

Figure 2: Principal components of brain RNAseq and microarray expression levels across four tissues. Each point represents one animal with shape indicating sex (circle = female, square = male) and color indicating genotype. For the F1 animals, the outer color indicates maternal strain and the inner color paternal strain. (a) PC1 versus PC2 of the brain RNAseq total read counts for all autosomal genes. The three inbred strains form a near-perfect triangle with the F1 samples located between their corresponding parental strains. PC1 and PC2 account for 31% of the variance in TReC, indicating that genetic background is the overwhelming driver of gene expression difference, greatly exceeding the effects of parent-of-origin and sex. (b) PC1 versus PC2 of microarray expression values for all autosomal genes across four tissues. The pattern seen in the brain extends to multiple diverse tissues.
Mentions: Within each tissue, the overwhelming driver of differential gene expression was strain; this greatly exceeded the effects of parent-of-origin and sex (Fig. 2). For RNAseq, the first two principal components (PCs) accounted for ~30% of the total variation in autosomal total read count (TReC). The remaining top 10 PCs were also strongly determined by strain and, to a far lesser extent, parent-of-origin and sex, with no notable effects of the barcodes used for multiplexing (Supplementary Table 3).

Bottom Line: Complex human traits are influenced by variation in regulatory DNA through mechanisms that are not fully understood.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

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.

Show MeSH
Related in: MedlinePlus