A survey of allelic imbalance in F1 mice - PubMed (original) (raw)

A survey of allelic imbalance in F1 mice

Catarina D Campbell et al. Genome Res. 2008 Apr.

Abstract

There are widespread, genetically determined differences in gene expression. However, methods that compare transcript levels between individuals are subject to trans-acting effects and environmental differences. By looking at allele-specific expression in the F1 progeny of inbred mice, we can directly test for allelic imbalance (AI), which must be due to cis-acting variants in the parental strains. We tested over one hundred genes for AI between C57Bl/6J and A/J alleles in F1 mice, including a validation set of 23 genes enriched for cis-acting variants and a second set of 92 genes whose orthologs were previously examined for AI in humans. We assayed an average of two transcribed SNPs per gene in liver, spleen, and brain from three male and three female F1 mice. In the set of 92 genes, we observed 33 genes (36%) with significant AI including genes with AI that was specific to certain tissues or transcripts. We also observed extensive tissue-specific AI, with 11 out of 92 genes (12%) having differences in AI between tissues. Interestingly, several genes with alternate transcripts have transcript-specific AI. Finally, we observed that the presence of AI in human genes was correlated to the presence of AI in the mouse orthologs (one-tailed P = 0.003), suggesting that certain genes may be more tolerant of cis-acting variation across species.

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Figures

Figure 1.

Figure 1.

Summary of genes tested and major findings.

Figure 2.

Figure 2.

Magnitude of allelic imbalance. The statistical significance from Wilcoxon rank sum tests (-log of the _P_-value) is plotted against the magnitude of AI (absolute value of the difference between 0.5 [no AI] and the average ratio B6/[AJ + B6]) for each of the 115 genes in each tissue. The dotted line indicates an empirical P = 0.05. Error bars are the standard error of the mean; genes with large standard errors have SNP differences in AI. (A) brain; (B) liver; (C) spleen.

Figure 3.

Figure 3.

Example of tissue-specific allelic imbalance in Emilin2. Representative spectra of a transcribed SNP assayed in F1 genomic DNA and cDNA from three tissues. The peak locations for the A/J and B6 alleles are marked. For this gene, the B6 allele peak is higher than the A/J allele peak in brain and spleen, but the A/J allele peak is higher than the B6 peak in liver.

Figure 4.

Figure 4.

Overlap of genes with allelic imbalance between tissues. For this analysis, only the 33 genes with any evidence of AI were considered. Three genes are represented twice in the diagram because two of the tissues had evidence for allelic imbalance favoring alleles from opposite strains.

Figure 5.

Figure 5.

Examples of transcript-specific allelic imbalance. Representations of the exon and UTR structures are plotted with the thicker bars symbolizing coding sequence and the thinner bars symbolizing UTR sequence. Exon numbers are given in the bars for each exon. These diagrams are based on information from the UCSC Genome Browser (genome.ucsc.edu). Below the representation of each gene, a graph of B6/(A/J + B6) is plotted for SNPs that fall within the exons shown. The horizontal line across each graph marks a 50:50 ratio of B6 to A/J alleles. (A) Ccnf has two transcripts that differ in 3′ UTR length; data shown are from spleen. (B) Brd8 has two transcripts that differ in 5′ UTR length; data shown are the average of all tissues. (C) Snx13 has two transcripts with different last exons and 3′ UTRs; data shown are the average of all tissues.

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