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., Morón B., Iwasaki J., Barton PR., Caetano S., Hng KI., Cambridge E., Forman S., Crockford TL., Griffiths M., Kane L., Harcourt K., Brandt C., Notley G., Babalola KO., Warren J., Mason JC., Meeniga A., Karp NA., Melvin D., Cawthorne E., Weinrick B., Rahim A., Drissler S., Meskas J., Yue A., Lux M., Song-Zhao GX., Chan A., Ballesteros Reviriego C., Abeler J., Wilson H., Przemska-Kosicka A., Edmans M., Strevens N., Pasztorek M., Meehan TF., Powrie F., Brinkman R., Dougan G., Jacobs W., Lloyd CM., Cornall RJ., Maloy KJ., Grencis RK., Griffiths GM., Adams DJ., Hayday AC.
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 (http://www.immunophenotype.org). Specifically, high-throughput phenotyping of 530 unique mouse gene knockouts identified 140 monogenic 'hits', of which most had no previous immunologic 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 each other and with specific physiologic traits. Such linkages limit freedom of movement for individual immune parameters, thereby imposing genetically regulated 'immunologic structures', the integrity of which was associated with immunocompetence. Hence, we provide an expanded genetic resource and structural perspective for understanding and monitoring immune variation in health and disease.