High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation.
journal contributionposted on 2020-10-22, 13:35 authored by Lucie Abeler-Dörner, Adam G Laing, Anna Lorenc, Dmitry S Ushakov, Simon Clare, Anneliese O Speak, Maria A Duque-Correa, Jacqueline K White, Ramiro Ramirez-Solis, Namita Saran, Katherine R Bull, Belén Morón, Jua Iwasaki, Philippa R Barton, Susana Caetano, Keng I Hng, Emma Cambridge, Simon Forman, Tanya L Crockford, Mark Griffiths, Leanne Kane, Katherine Harcourt, Cordelia Brandt, George Notley, Kolawole O Babalola, Jonathan Warren, Jeremy C Mason, Amrutha Meeniga, Natasha A Karp, David Melvin, Eleanor Cawthorne, Brian Weinrick, Albina Rahim, Sibyl Drissler, Justin Meskas, Alice Yue, Markus Lux, George X Song-Zhao, Anna Chan, Carmen Ballesteros Reviriego, Johannes Abeler, Heather Wilson, Agnieszka Przemska-Kosicka, Matthew Edmans, Natasha Strevens, Markus Pasztorek, Terrence F Meehan, Fiona Powrie, Ryan Brinkman, Gordon Dougan, William Jacobs, Clare M Lloyd, Richard J Cornall, Kevin J Maloy, Richard K Grencis, Gillian M Griffiths, David J Adams, Adrian C Hayday
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.