Abstract
Creation of lethal and synthetic lethal mutations in an experimental organism is a cornerstone of genetic dissection of gene function, and is related to the concept of an essential gene. Common inbred mouse strains carry background mutations, which can act as genetic modifiers, interfering with the assignment of gene essentiality. The inbred strain C57BL/6J, commonly known as “Black Six”, stands out, as it carries a spontaneous homozygous deletion in the nicotinamide nucleotide transhydrogenase (Nnt) gene [GenBank: AH009385.2], resulting in impairment of steroidogenic mitochondria of the adrenal gland, and a multitude of indirect modifier effects, coming from alteration of glucocorticoid-regulated processes. Over time, the popular strain has been used, by means of gene targeting technology, to assign “essential” and “redundant” qualifiers to numerous genes, thus creating an internally consistent “parallel universe” of knowledge. It is unrealistic to suggest phasing-out of this strain, given the scope of shared resources built around it, however, continuing on the road of “strain-unawareness” will result in profound waste of effort, particularly where translational research is concerned. The review analyzes the historical roots of this phenomenon and proposes that building of “parallel universes” should be urgently made visible to a critical reader by obligatory use of unambiguous and persistent tags in publications and databases, such as hypertext links, pointing to a vendor’s strain description web page, or to a digital object identifier (d.o.i.) of the original publication, so that any research done exclusively in C57BL/6J, could be easily identified.ReviewersThis article was reviewed by Dr. Neil Smalheiser and Dr. Miguel Andrade-Navarro.
Highlights
The concept of an essential gene, whose targeted inactivation results in lethality of a genetically modified organism, is a cornerstone of genetic dissection of gene function
Substantial data has accumulated that the peculiar properties of certain targeted mutations on the C57BL/6J background are not seen when the mutation is expressed on the background of other popular strains such as FVB/N or 129/Sv, or mixed mouse backgrounds, or even in the patient, whose disease was modeled in the mouse
If Hans Selye [85] were alive today, he would have certainly been deeply concerned by the fact that a mouse strain with a remodeled stress response and an impaired hypothalamic-pituitary-adrenal axis is used in the 21st century as a reference in hundreds of laboratories worldwide
Summary
A major portion of our current knowledge about gene function in mammals is derived from the phenotypes of mouse strains with targeted or random gene inactivation [9]. Publications since 2012 of multiple mouse strain sequences derived by generation sequencing technology have revealed a number of point mutations and insertions/ deletions in many, if not all, of the popular strains, the scope of which does not correlate with the apparent “normality” of the mice [21] Such discoveries question the importance of studies of the point mutation of just one peculiar gene. Substantial data has accumulated that the peculiar properties of certain targeted mutations on the C57BL/6J background are not seen when the mutation is expressed on the background of other popular strains such as FVB/N or 129/Sv, or mixed (hybrid) mouse backgrounds, or even in the patient, whose disease was modeled in the mouse Such examples are too numerous to be comprehensively included here, without a bias toward a specific field or research group. Despite the existence of the ARRIVE guidelines for animal research [84] that emphasize the importance of correct animal identity, only a few journals have adopted them
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
