In the name of reproducibility

Adhering to mouse nomenclature guidelines ensures that research is discoverable, replicable, and less wasteful. So why don’t researchers do it? Main John Sundberg, a 67-year-old veterinary pathologist at The Jackson Laboratory in Bar Harbor, Maine, is an unyielding enforcer of mouse nomenclature. He points out discrepancies with accepted norms in almost every paper that he reviews and is wont to publicly rebuke speakers at conferences for referring to incorrect genes and strains. The same, but different: They may all be the same species, but lab mice can vary genetically. Proper nomenclature is critical to account for those differences. Credit: (ocipalla / iStock / Getty Images Plus) That goes for his employer too. A few years ago, he called out a colleague for his laxity in citing ‘Jax lab’. “I brought to his attention that the official name of this institution is ‘The’ Jackson Laboratory,” says Sundberg. Dropping the definite article, he told the man, risked confusing the biomedical research institute with an Indian pharmaceutical company or an American antibodies manufacturer, both called some variation of “Jackson lab”. Sundberg’s pedantry is encouraged at The Jackson Laboratory, the global custodian of mouse-related terminology. As the institute’s newest hire, Sundberg was himself the subject of such censure. In 1988, he had recently published a paper on the mouse papillomavirus in which he had failed to explicate the full strain name of a mouse model. It didn’t take long for his colleagues to inform him that all papers were to be reviewed for naming accuracy prior to publication. “I got my knuckles snapped.” Sundberg now feels morally obliged to uphold the laboratory’s high standards. “I am carrying the torch now; it is my turn to try to make people understand the significance of doing things correctly.” But the work of protocol purists like Sundberg is becoming ever more difficult as genetic research advances and more and more researchers adopt mouse models in their experiments. “The level of ignorance is the same, but the level of complexity of mammalian genetics has grown exponentially,” he says. Sundberg remembers receiving a complaint call regarding nude mice. These mice lack a type of white blood cell called T cells, which makes them ideal for tissue transplant studies. But the caller’s specimens had all rejected the transplant. “Turns out the person who had ordered the mice had requested hairless mice, which are cheaper, but only have a mild T cell abnormality,” says Sundberg. The biomedical literature is rife with such lapses in clarity. At the pre-publication stage, Sundberg and other reviewers claim papers that get it right are the exception. A 2013 study, led by biocurator and ontologist Nicole Vasilevsky at Oregon Health & Science University, attempted to quantify the scale of the nomenclature problem1. In a review of 238 articles in 84 journals, Vasilevsky and her colleagues found that mouse models could be identified in only 67% of mentions. For the remaining 33%, a researcher unconnected to the study would not be able to obtain the resources to reproduce the experiments just from the information provided in the published paper. “From reading papers every day, the use of standardized nomenclature is very spotty; it is certainly not consistent,” says Caroline Zeiss, a veterinary pathologist at Yale School of Medicine. Yet, “of all the variables that affect reproducibility, the use of standardized nomenclature is one of the easiest fixes.” So what are the rules? Kinky and wobbly When geneticist Muriel Davisson created a new mouse model for Down syndrome in 1990, she assigned the name and registered it herself. She was familiar with the protocols, having been responsible for approving new mutations and gene names at The Jackson Laboratory till her retirement in 2012. Standard nomenclature for mouse models includes details on the strain of the mouse, the lab in which it originated and those it is maintained in, as well as the type and name of mutations it contains (Table 1). The Mouse Genome Informatics (MGI) project at The Jackson Laboratory is the ultimate resource for genetic, genomic, and biological information about the laboratory mouse. Also housed at The Jackson Laboratory is the International Mouse Strain Resource, which collates information about where to find mice that are available from commercial vendors or public mouse strain repositories. Laboratory codes are designated by the International Laboratory Code Registry, maintained by the United States National Academies of Sciences, Engineering, and Medicine. MGI coordinates with these and other collections to maintain its database. Table 1 What’s in a name? Some questions to consider: Full size table Davisson’s Down syndrome model was named Ts(1716)65Dn. Ts for trisomic, because it contains three copies of parts of chromosomes 16 and 17. It is the 65th chromosomal aberration discovered in Davisson’s lab, registered with the code Dn. Other investigators have crossed it into other genetic backgrounds, or combined it with other mutations, so there are a number of different strains that carry this chromosomal aberration registered in MGI. Two repository strains that carry this chromosomal rearrangement include B6EiC3Sn.BLiA-Ts(1716)65Dn/DnJ and B6EiC3Sn a/A-Ts(1716)65Dn/J. That name is the culmination of decades of work. Standards for referring to mouse genetic information were first published in September 1939 by a newly convened Committee on Mouse Genetics Nomenclature, now known as the International Committee on Standardized Genetic Nomenclature for Mice. The committee decided the original rules by ballot, with 23 out of 43 members voting to use symbols based on the first initial of the gene of interest, such as dw for the dwarf gene, and expressed in italics. The guidelines included details on how to distinguish between recessive and dominant genes, as well as alleles. Initially, researchers kept abreast of new genetic discoveries via an informal biannual (and later quarterly) bulletin launched in 1949, known as Mouse News Letter. “It was quaint,” says bioinformatician Janan Eppig, who managed the MGI database from its inception till her retirement last year. The newsletters published updates from labs all over the world—the first edition described mutants named kinky, wobbly, trembler, and paralytic. “It would include everything from, ‘I found this new gene that makes purple spots’ to ‘so-and-so has moved from my lab over to so-and-so’s lab’.” Details about nomenclature and new gene discovery ensured, says Eppig, “that each gene that was discovered had its own unique identity.” Harwell (now known as MRC Harwell Institute) published the newsletter for 48 years, by which time The Jackson Laboratory had set up its own Encyclopedia of the Mouse Genome, a precursor to MGI2. Initially released in 1990, before the large-scale adoption of the World Wide Web, th (...truncated)