Gene variant activity is surprisingly variable between tissues

Every gene in (almost) every cell of the body is present in two variants - so called alleles: one is deriving from the mother, the other one from the father. In most cases both alleles are active and transcribed by the cells into an RNA message. However, for a few genes, only one allele is expressed, while the other one is silenced. The decision whether the maternal or the paternal version is shut down occurs early in embryonic development - one reason, why for long it was thought that the pattern of active alleles is nearly homogeneous in the various tissues of the organism.

The new study, 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.

Andergassen D, Dotter CP, Wenzel D, Sigl V, Bammer PC, Muckenhuber M, Mayer D, Kulinski TM, Theussl HC, Penninger JM, Bock C, Barlow DP, Pauler FM, Hudson QJ.
Mapping the mouse Allelome reveals tissue-specific regulation of allelic expression.
Elife. 2017 Aug 14;6. pii: e25125. doi: 10.7554/eLife.25125.

Most Popular Now

Most popular vitamin and mineral supplements provi…

The most commonly consumed vitamin and mineral supplements provide no consistent health benefit or harm, suggests a new study led by researchers at St. Michael's Hospital...

AstraZeneca heads to 2018 ASCO Annual Meeting with…

AstraZeneca and MedImmune, its global biologics research and development arm, head to the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, US...

Tiny particles could help fight brain cancer

Glioblastoma multiforme, a type of brain tumor, is one of the most difficult-to-treat cancers. Only a handful of drugs are approved to treat glioblastoma, and the median ...

New approach to immunotherapy leads to complete re…

A novel approach to immunotherapy developed by researchers at the National Cancer Institute (NCI) has led to the complete regression of breast cancer in a patient who was...

Amgen Foundation and Harvard team up to offer free…

The Amgen Foundation and Harvard University today announced plans to launch a free online science education platform uniquely designed to level the playing field for aspi...

The Pfizer Foundation announces $5 million in gran…

The Pfizer Foundation announced a new $5 million grant commitment to initiatives in low- and middle-income countries that provide family planning access and education for...

Study finds antioxidant-enriched vitamin reduces r…

Researchers at Children's Hospital Colorado (Children's Colorado) and the University of Colorado School of Medicine have found that taking a specially formulated antioxid...

New drugs could also be deployed against lung and …

A new anti-cancer drug may be effective against a wider range of cancers than previously thought. Using a mouse model and samples taken from cancer patients, a team from ...

What would help or hinder patient participation in…

As clinical trials gear up with the aim of attaining the first FDA-approved treatments for mitochondrial disease, a new study reports for the first time what patients and...

Pfizer to expand venture investing with $600 milli…

Pfizer Inc. (NYSE:PFE) today announced it plans to invest $600 million in biotechnology and other emerging growth companies through Pfizer Ventures, the company’s venture...

Update on Phase III clinical trials of lanabecesta…

AstraZeneca and Eli Lilly and Company (Lilly) are discontinuing the global Phase III clinical trials of lanabecestat, an oral beta secretase cleaving enzyme (BACE) inhibi...

Soy lecithin NSAID combo drug protects against can…

When scientists at The University of Texas Health Science Center at Houston (UTHealth) applied a chemical found in soybeans to a non-steroidal anti-inflammatory drug (NSA...