Two major studies by international teams published today (June 26) show the value and potential of genetically modified mice in biomedical research — and also the pitfalls of conducting research with subjects of only one sex. Researchers at the University of California, Davis, Mouse Biology Program collaborated on both studies, published in the journals Nature Genetics and Nature Communications.
The Mouse Biology Program, led by Professor Kent Lloyd, is a member of the International Mouse Phenotyping Consortium, or IMPC. The UC Davis contributions to the research included making embryonic stem cells used to breed genetically modified mice, and characterizing the effects of those genetic changes on mice.
“The MBP is one of only a very few places in the United States and the world with the expertise, technology, infrastructure and capacity to undertake a project of this magnitude and importance for science and for precision medicine,” Lloyd said.
First 3,328 genes reveal 360 disease models
The IMPC is aiming to produce a complete catalog of all genes in the laboratory mouse. For the Nature Genetics paper they characterized the first 3,328 genes identified, equivalent to about 15 percent of the mouse genome. More than half of these genes had not been studied before, and almost 1,100 had no previously known function.
The study produced more than 28,000 new descriptions of genes’ effects on health and disease in the mouse. From this, they could identify 360 mutant mice that are potential models of human inherited diseases including a blood-clotting disorder, a form of heart disease and neurodegenerative diseases. Identifying causative genes for rare inherited diseases could speed the development of treatments.
With its similarity to human biology and ease of genetic modification, the laboratory mouse is arguably the preferred model for studying human genetic disease, but most of the mouse genome remains poorly understood. The IMPC is aiming to build a complete database that systematically details the functions of all areas of the mouse genome, including neurological, metabolic, cardiovascular, respiratory and immunological systems.
The project involves going through the mouse genome and systematically knocking out specific genes, one by one, in different mice. By looking at the mouse’s characteristics in a battery of standardized tests, the team can see if and how the gene knockout manifests itself as a disease, and link their findings to what is already known about the human version of the disease.
“These 360 new disease models that we’ve identified in mice represent the first steps of a hugely important international project. We hope researchers will be able to use this knowledge to develop new therapies for patients, which is ultimately what we’re all striving to achieve,” said lead author Damian Smedley from Queen Mary University of London.
Differences between male and female mice
Sex is known to have a profound impact on physiology and response to diseases including cardiovascular disease, autoimmune disease and asthma. Yet medical research tends to focus on males in both human and animal studies and assume that what is true for one sex holds for the other.
In the second study, researchers looked across multiple experiments to assess 234 characteristics including bone mass, body composition, metabolic profile, blood components, behavioral traits and shape of body parts in more than 50,000 normal (control) and mutant mice.
In control mice, sex affected 56.6 percent of quantitative traits such as bone mass, and 9.9 percent of qualitative traits such as head shape.
In mutant mice, the researchers looked for an additional influence of sex on the effect of the mutation. They found that sex had an impact on 17.7 percent of mutations in quantitative traits and 13.3 percent of mutations in qualitative traits.
The UC Davis team, for example, showed that knocking out a gene called GdF2 (growth differentiation factor 2) caused cardiomegaly, or enlargement of the heart, in female but not in male mice.
The study shows how often sex differences occur in traits that we would otherwise assume to be the same in males and females, said co-author Judith Mank, University College London.
“The fact that a mouse’s sex influenced the effects of genetic modification indicates that males and females differ right down to the underlying genetics behind many traits,” she said.
The International Mouse Phenotyping Consortium includes 15 research institutes and centers worldwide, including UC Davis. Additional authors were from the Wellcome Trust Sanger Institute and the European Bioinformatics Institute (both located in Cambridge, U.K.), Medical Research Council Harwell (U.K.), University College London, Queen Mary University London and Oregon Health Sciences University. The work was supported by grants from the National Institutes of Health and Wellcome.