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

Fasenra (benralizumab) receives US FDA approval fo…

AstraZeneca and its global biologics research and development arm, MedImmune, announced that the US Food and Drug Administration (FDA) has approved Fasenra (benralizumab)...

Pfizer receives FDA approval for SUTENT® (sunitini…

Pfizer Inc. (NYSE:PFE) today announced that the U.S. Food and Drug Administration has approved a new indication expanding the use of SUTENT® (sunitinib malate) to include...

Alzheimer's disease might be a 'whole body' proble…

Alzheimer's disease, the leading cause of dementia, has long been assumed to originate in the brain. But research from the University of British Columbia and Chinese scie...

Cancer cells destroyed with dinosaur extinction me…

Cancer cells can be targeted and destroyed with the metal from the asteroid that caused the extinction of the dinosaurs, according to new research by an international col...

Novartis confirms leadership in multiple sclerosis…

Novartis today announced it will present 54 scientific abstracts from across its multiple sclerosis (MS) research portfolio at the 7th Joint European and Americas Committ...

Amgen and Novartis announce expanded collaboration…

Amgen (NASDAQ:AMGN) and Novartis announced an expanded collaboration with the Banner Alzheimer's Institute (BAI) to initiate a new trial - the Alzheimer's Prevention Init...

Transplanted hematopoietic stem cells reverse dama…

Researchers at University of California San Diego School of Medicine report that a single infusion of wildtype hematopoietic stem and progenitor cells (HSPCs) into a mous...

Novartis announces the planned acquisition of Adva…

Novartis announced today, that it has entered a memorandum of understanding with Advanced Accelerator Applications (AAA) under which Novartis intends to commence a tender...

New tissue-engineered blood vessel replacements on…

Researchers at the University of Minnesota have created a new lab-grown blood vessel replacement that is composed completely of biological materials, but surprisingly doe...

'Precision Medicine' may not always be so precise

Precision Medicine in oncology, where genetic testing is used to determine the best drugs to treat cancer patients, is not always so precise when applied to some of the w...

New US study reveals key reasons why millions of p…

Few of the more than 90 million Americans(1) with obesity are seeking and receiving long-term obesity care, according to new data from the Awareness, Care and Treatment I...

Efficacy and safety maintained in patients who swi…

Boehringer Ingelheim today announced one-year data from VOLTAIRE®-RA, a pivotal Phase III clinical trial comparing Cyltezo® (adalimumab-adbm) and reference product Humira...

Pharmaceutical Companies

[ A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Z ]