High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation

By developing a high-density murine immunophenotyping platform compatible with high-throughput genetic screening, we have established profound contributions of genetics and structure to immune variation (www.immunophenotype.org). Specifically, high- throughput phenotyping of 530 unique mouse gene knockouts identified 140 monogenic “hits”, of which most had no previous immunological association. Furthermore, hits were collectively enriched in genes for which humans show poor tolerance to loss-of-function. The immunophenotyping platform also exposed dense correlation networks linking immune parameters with one another and with specific physiologic traits. Such linkages limit freedom-of-movement for individual immune parameters, thereby imposing genetically regulated “immunological structures”, whose integrity was associated with immunocompetence. Hence, we provide an expanded genetic resource and structural perspective for understanding and monitoring immune variation in health and disease.