The NIH Common Fund Knockout Mouse Phenotyping Program (KOMP2) collaborates with the International Mouse Phenotyping Consortium (IMPC) (link is external) to knockout (remove) and characterize all protein-coding genes in the mouse genome. Overall, this project helps scientists explain the genetic basis of many different types of diseases that occur in both mice and humans, including under-studied rare diseases and common chronic diseases that affect much of the human population. This collaborative effort has been a powerful resource for describing genes with previously unknown function in hearing, embryonic development, and metabolism, for example. Now, KOMP2 researchers gained new insights on the genetics of the immune system. In addition to a standardized phenotyping of each knockout, or looking at the physical characteristics of the mice, researchers in this study carried out extra tests to more closely investigate the immune system in knockout mice. This included adding specialized tests to look at immune cell activity in the lymphatic system, the organs in the body that control the immune system, as well as testing how exposure to viral, bacterial, and parasite pathogens alters immune responses.
In this study, 25% of the 530 genes studied revealed observable differences in immune cell phenotypes. Furthermore, more than half of the genes with these immune phenotypes had no previous known link to immune system function, indicating important new discovery opportunities made possible by using these approaches. In this analysis, even well-studied genes, for example Bach2, had new phenotypes that may contribute to disease mechanisms. Collectively, these findings illustrate the value of a large-scale immune system screen to identify previously unrecognized components of immune system development and regulation, as well as uncover additional roles for known genes. Importantly, most of the mouse genes identified had a human counterpart gene that was known to be important, but not necessarily recognized to be involved in immune system regulation. This is consistent with the potential that further exploration of the genes identified will have meaningful relevance to human health.
Reference
- High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation. Abeler-Dörner L, Laing AG, Lorenc A, Ushakov DS, Clare S, Speak AO, Duque-Correa MA, White JK, Ramirez-Solis R, Saran N, Bull KR. Nat Immunol 21, 86–100 (2020).
