Of Mice and Men: Study Pinpoints Genes Essential for Life

Many people probably think of mice as unwanted household pests. But over more than a century, mice have proven to be incredibly valuable in medical research. One of many examples is how studies in mice are now helping researchers understand how mammalian genomes work, including the human genome. Scientists have spent decades inactivating, or “knocking out,” individual genes in laboratory mice to learn which tissues or organs are affected when a specific gene is out of order, providing valuable clues about its function.

More than a decade ago, NIH initiated a project called KOMP—the Knockout Mouse Project [1]. The goal was to use homologous recombination (exchange of similar or identical DNA) in embryonic stem cells from a standard mouse strain to knock out all of the mouse protein-coding genes. That work has led to wide availability of such cell lines to investigators with interest in specific genes, saving time and money. But it’s one thing to have a cell line with the gene knocked out, it’s even more interesting (and challenging) to determine the phenotype, or observable characteristics, of each knockout. To speed up that process in a scientifically rigorous and systematic manner, NIH and other research funding agencies teamed to launch an international research consortium to turn those embryonic stem cells into mice, and ultimately to catalogue the functions of the roughly 20,000 genes that mice and humans share. The consortium has just released an analysis of the phenotypes of the first 1,751 new lines of unique “knockout mice” with much more to come in the months ahead. This initial work confirms that about a third of all protein-coding genes are essential for live birth, helping to fill in a major gap in our understanding of the genome.

The finding comes from the International Mouse Phenotyping Consortium. It involved a team of scientists on three continents, led by Stephen Murray, Jackson Laboratory, Bar Harbor, ME and other outstanding researchers, some of whom are highlighted in the links below.

As described in their paper, published recently in the journal Nature, this team of researchers utilized embryonic stem cell resources to develop 1,751 strains of knockout mice that had never been studied before, each carrying two inactivated copies of a different gene on an otherwise identical genetic background. Their studies showed that the loss of 410 of those first 1,751 genes were incompatible with live birth [2].

To learn more about those essential genes, the researchers developed a comprehensive approach for defining the precise timing of embryonic death. They also applied the latest in high-resolution, 3D imaging technology to detect developmental problems that might have otherwise gone unnoticed.

The most commonly observed abnormalities included slowed growth and embryonic development. They also saw many abnormalities in cardiovascular development, malformations of the head and face, and defects in limb development.

As evidence to suggest the findings are relevant to understanding human disease, the researchers showed that loss-of-function mutations for those essential mouse genes are rarely found in the corresponding genes of living people. The finding suggests those genes are also essential to human life and health and could be good places to look for answers to miscarriages, stillbirths, or unexplained genetic conditions in people.

There were some surprises, too. Despite the fact that researchers in the consortium all conducted their studies according to standardized protocols, embryonic mice carrying exactly the same set of genes didn’t always share the same physical features or experience the same life or death outcomes. The findings suggest that in addition to genes and environmental factors, other seemingly random events during development can also play an important role.

The work is ongoing. In fact, the consortium already has data on hundreds more knockout mice available, just waiting to be analyzed. All of the data is being openly provided in real time to investigators around the world to explore and expand on as needed. The consortium is also making the knockout mice themselves available to enable other researchers with particular interests to study them in even greater detail.

It goes to show the remarkable progress to be made in biomedicine when researchers around the world rally as a team around a common approach to achieve a common goal. That’s a great take-home message.

References:

[1] Knockout Mouse Project (KOMP) Repository (University of California, Davis and Children’s Hospital Oakland Research Institute)

[2] High-throughput discovery of novel developmental phenotypes. Dickinson ME, Flenniken AM, Ji X, Teboul L, Wong MD, White JK, Meehan TF, Weninger WJ, Westerberg H, Adissu H, Baker CN, Bower L, Brown JM, Caddle LB, Chiani F, Clary D, Cleak J, Daly MJ, Denegre JM, Doe B, Dolan ME, Edie SM, Fuchs H, Gailus-Durner V, Galli A, Gambadoro A, Gallegos J, Guo S, Horner NR, Hsu CW, Johnson SJ, Kalaga S, Keith LC, Lanoue L, Lawson TN, Lek M, Mark M, Marschall S, Mason J, McElwee ML, Newbigging S, Nutter LM, Peterson KA, Ramirez-Solis R, Rowland DJ, Ryder E, Samocha KE, Seavitt JR, Selloum M, Szoke-Kovacs Z, Tamura M, Trainor AG, Tudose I, Wakana S, Warren J, Wendling O, West DB, Wong L, Yoshiki A; International Mouse Phenotyping Consortium; Jackson Laboratory; Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS); Charles River Laboratories; MRC Harwell; Toronto Centre for Phenogenomics; Wellcome Trust Sanger Institute; RIKEN BioResource Center, MacArthur DG, Tocchini-Valentini GP, Gao X, Flicek P, Bradley A, Skarnes WC, Justice MJ, Parkinson HE, Moore M, Wells S, Braun RE, Svenson KL, de Angelis MH, Herault Y, Mohun T, Mallon AM, Henkelman RM, Brown SD, Adams DJ, Lloyd KC, McKerlie C, Beaudet AL, Bućan M, Murray SA. Nature. 2016 Sep 14.

Links:

International Mouse Phenotyping Consortium

International Knockout Mouse Consortium

Knockout Mice Fact Sheet (National Human Genome Research Institute/NIH)

Steve Murray (The Jackson Laboratory, Bar Harbor, ME)

Mary Dickinson (Baylor College of Medicine, Houston)

The Centre for Phenogenomics (Toronto, Canada)

Medical Research Council Harwell (Oxfordshire, U.K.)

Maja Bucan (University of Pennsylvania, Philadelphia)

NIH Support: National Human Genome Research Institute; Common Fund