Gene variant activity is surprisingly variable between tissues

The new study (DOI:10.7554/eLife.25125), where CeMM PhD Student Daniel Andergassen is first author (now a PostDoc at Harvard University), uncovers a different picture. By performing the first comprehensive analysis of all active alleles in 23 different tissues and developmental stages of mice, the team of scientists revealed that each tissue showed a specific distribution of active alleles.

For their experiments, the researchers created hybrids of two genetically distinct mouse strains with a fully sequenced genome, allowing gene variants to be clearly assigned to the maternal or paternal allele. To facilitate the analysis, the team developed a user-friendly program called Allelome.PRO, that can easily be applied to similar datasets in mice and other species, a valuable tool for the community to investigate regulation of allele activity. By using this tool to analyze their data the scientists were able to catalogue active alleles in a comprehensive set of mouse tissues, or the mouse "Allelome," and gain an insight into how this differential gene activity is regulated.

The scientists found that both genetic and epigenetic differences between the maternal and paternal allele contributed to the observed tissue-specific activity patterns. "Our results indicate that a large part of those patterns are induced by so-called 'enhancers'," co-senior author Quanah Hudson, now at IMBA (Institute for molecular Biotechnology of the Austrian Academy of Sciences) explains. "Enhancers are DNA regions that are often located at quite some distance from the observed allele, but nevertheless have a direct influence on their activity."

"This study reveals for the first time a comprehensive picture of all active alleles in different tissues -- we have uncovered the first complete allelome" Florian Pauler, now at ISTA (Institute of Science and Technology Austria) and co-senior author, adds. "This is not only valuable to understand basic biological functions, but will also help investigating diseases that involve defective gene regulators."

Some of the genes that contributed to the tissue-specific activity patterns were located on the X chromosome and escaped so-called "X-chromosome inactivation," where one of the two X chromosomes in females gets shut down. Previously it was reported that around 3% of X-chromosomal genes in mice and 15% in humans escape inactivation. However, this study revealed that mice are more similar to humans than previously thought, with an average of around 10% of active genes escaping X-inactivation per tissue. By examining a broad range of organs the researchers showed that the number of escapers varies dramatically between tissues. Most strikingly, muscle showed a surprisingly high rate of escapers, with over 50% of active genes escaping X chromosome activation, a result that may be relevant to some diseases of the muscle.

Finally, the allelome offers a near complete picture of "genomic imprinting," the process that leads to epigenetic silencing of either the maternal or paternal allele that is initiated by an epigenetic mark placed in either the egg or sperm. Previously, it was reported that approximately 100 genes can be subject to imprinted silencing -- but in many cases, the tissue specificity was not known. This study led to the discovery of 18 new imprinted genes, validated some known genes and resolved the disputed status of some others to provide a gold standard list of 93 imprinted genes in mouse. The scientists found that those new genes were located near to other imprinted genes, indicating that they were co -- regulated. Interestingly, this study demonstrated that Igfr2, the first imprinted gene discovered by Denise Barlow in 1991, is surrounding by a large cluster of imprinted genes that extend over 10% of the chromosome, making it the largest co-regulated domain in the genome outside of the X chromosome. Fittingly, after her lab found the first imprinted gene, and discovered the first imprinted non-coding RNA shown to control imprinted silencing. Giulio Superti-Furga congratulates Denise Barlow who recently went into retirement to her great scientific achievements and for revealing the full picture of imprinted genes in the mouse.