A genomic balancing act
Allelic expression in the mouse genome is surprisingly unbalanced, according to new research published in the June issue of GENETICS.
The factors that determine how a gene is expressed in a given cell are complex. After all, every mammalian cell contains two copies of each gene, and both versions of that gene, called alleles, play a part in bringing that gene’s message to life. It seems natural to assume that each allele contributes equally to the overall genetic output, and in large part, that’s true. Known exceptions to the rule, however, include X-inactivation (random inactivation of one of the two copies of the X-chromosome in female mammals), random but stable monoallelic expression (which ensures cellular heterogeneity, like in olfaction), and imprinting (where expression depends on whether the allele was inherited from the father or the mother). But these cases are independent of the alleles’ genotypes; it doesn’t matter whether the two alleles are identical or different. The new GENETICS study shows that allelic imbalance caused by genetic differences is far from an exception; in fact, depending on the level of genetic diversity, about 20% of the mouse genome can be preferentially expressed from one allele over the other.
Pinter et al. used RNA sequencing to search the mouse genome for allelic imbalance. As part of this approach, the researchers crossed different subspecies of mice—which differ genetically at many genes—and analyzed the transcriptomes of the parents and the hybrid offspring. Using the parental genome sequence, they were able to track transcripts back to their allele of origin and identify those that showed a reproducible imbalance between alleles. They then tested whether expression was skewed randomly, according to an allele’s parent-of-origin (i.e., whether the gene was imprinted), or by genotype. The mouse is a great model for such studies since both genotype and parental origin can be switched. Remarkably, one-fifth of autosomal genes in this mouse cross were shown to have genotypically imbalanced expression, or GTIE, in which one allele was expressed more than the other according to genotype.
Pinter et al. also found that the alleles of imbalanced genes tend to be more divergent than those of balanced genes. This suggests the likelihood of a given gene’s expression being imbalanced is proportional to how divergent its two alleles are.
Cells control gene expression through a complex system of genetic and epigenetic regulation; the level at which any given gene is expressed at a particular time and place is a delicate balancing act. Allelic imbalance is one of the newer pieces of this puzzle. The researchers suggest that GTIE may play a role in trait penetrance, the likelihood that an organism carrying a particular variant will express the associated trait. Because many human diseases show variable trait penetrance, extensive allelic imbalance may well prove clinically relevant.
Pinter, S. F., Colognori, D., Beliveau B. J., Sadreyev, R. I., Payer, B., Yildirim, E., Wu, C., & Lee, J. T. (2015) Allelic Imbalance Is a Prevalent and Tissue-Specific Feature of the Mouse Transcriptome. Genetics, 200(2), 537-549. doi: 10.1534/genetics.115.176263 http://www.genetics.org/content/200/2/537.full