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

Abeler-Dörner, L. et al. (2020) High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation. Nature Immunology, 21(1), pp. 86-100. (doi: 10.1038/s41590-019-0549-0) (PMID:31844327)

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 (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.

• Item Type: Articles
• Additional Information: The project was funded by a Wellcome Trust grant (no. 100156/Z/12/Z). M.D.-C. received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska–Curie grant agreement no. 656347. K.O.B., J.W. and T.M. were supported by the National Institutes of Health (NIH) Common Fund (grant no. UM1 HG006370). The development of automated flow analysis in R.B.’s group was supported by Genome BC (grant no. SOF152), the Natural Sciences and Engineering Research Council of Canada, the International Society for Advancement of Cytometry Genome Canada, Genome BC (grant no. 252FLO), the National Institute of General Medical Sciences (grant no. R01GM118417) and the Canadian Institutes of Health Research. G.D. was supported by a National Institute for Health Research grant to the Cambridge Biomedical Centre. W.J. was supported by an NIH grant (no. AI026170). C.M.L. is supported by a Wellcome Senior Fellowship in Basic Biomedical Science (no. 107059/Z/15/Z). R.J.C. is a principal investigator of the Medical Research Council’s Human Immunology Unit. K.J.M. is funded by a Wellcome Trust Investigator Award (no. 102972/Z/13/Z). R.K.G. holds a Wellcome Trust Investigator Award (no. Z10661/Z/18/Z) and is part of the Wellcome Trust Centre for Cell Matrix Research funded by an award (no. Z03128/Z/16/Z). In addition, the project was supported by grants and facilities provided to A.C.H. by the Francis Crick Institute, which receives its core funding from Cancer Research UK (grant no. FC001093), the UK Medical Research Council (grant no. FC001093) and the Wellcome Trust (grant no. FC001093).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Maloy, Professor Kevin
• Authors: Abeler-Dörner, L., Laing, A. G., Lorenc, A., Ushakov, D. S., Clare, S., Speak, A. O., Duque-Correa, M. A., White, J. K., Ramirez-Solis, R., Saran, N., Bull, K. R., Morón, 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. X., Chan, A., Ballesteros Reviriego, C., Abeler, J., Wilson, H., Przemska-Kosicka, A., Edmans, M., Strevens, N., Pasztorek, M., Meehan, T. F., Powrie, F., Brinkman, R., Dougan, G., Jacobs, W., Lloyd, C. M., Cornall, R. J., Maloy, K. J., Grencis, R. K., Griffiths, G. M., Adams, D. J., and Hayday, A. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Nature Immunology
• Publisher: Nature Publishing Group
• ISSN: 1529-2908
• ISSN (Online): 1529-2916
• Published Online: 16 December 2019