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

Abeler-Dörner, L.; Laing, A.; Lorenc, A.; Ushakov, D. S.; Clare, S.; Speak, A.; Duque, M.; White, J. K.; Ramirez-Solis, R.; Saran, N.; Bull, K. R.; Moron, B.; Iwasaki, J.; Barton, P. R.; Caetano, S.; Hng, K. I.; Cambridge, E.; Forman, S.; Crockford, T. L.; Griffiths, M.; Kane, L.; Harcourt, K.; Brandt, C.; Notley, G.; Babalola, K. O.; Warren, J.; Mason, J. C.; Meeniga, A.; Karp, N. A.; Melvin, D.; Cawthorne, E.; Weinrick, B.; Rahim, A.; Drissler, S.; Meskas, J.; Yue, A.; Lux, M.; Song-Zhao, G.; Chan, A.; Ballesteros Reviriego, C.; Abeler, J.; Wilson, H.; Przemska-Kosicka, A.; Edmans, M.; Stre

doi:10.1101/688010

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bioRxiv · 10.1101/688010

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

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Abstract

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. Specifically, high-throughput phenotyping of 530 knockout mouse lines identified 140 monogenic \"hits\" (>25%), most of which had never hitherto been implicated in immunology. Furthermore, they were conspicuously 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. By limiting the freedom of individual immune parameters, such linkages impose genetically regulated \"immunological structures\", whose integrity was found to be associated with immunocompetence. Hence, our findings provide an expanded genetic resource and structural perspective for understanding and monitoring immune variation in health and disease.

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Abeler-Dörner, L., Laing, A., Lorenc, A., Ushakov, D. S., Clare, S., Speak, A., Duque, M., White, J. K., Ramirez-Solis, R., Saran, N., Bull, K. R., Moron, B., Iwasaki, J., Barton, P. R., Caetano, S., Hng, K. I., Cambridge, E., Forman, S., Crockford, T. L., Griffiths, M., Kane, L., Harcourt, K., Brandt, C., Notley, G., Babalola, K. O., Warren, J., Mason, J. C., Meeniga, A., Karp, N. A., Melvin, D., Cawthorne, E., Weinrick, B., Rahim, A., Drissler, S., Meskas, J., Yue, A., Lux, M., Song-Zhao, G., Chan, A., Ballesteros Reviriego, C., Abeler, J., Wilson, H., Przemska-Kosicka, A., Edmans, M., Stre. 2019-07-02. High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation. https://doi.org/10.1101/688010

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