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

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

doi:10.1038/s41590-019-0549-0

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

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 GriffithsLeanne 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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 (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.

Original language	English
Pages (from-to)	86-100
Number of pages	15
Journal	Nature Immunology
Volume	21
Issue number	1
DOIs	https://doi.org/10.1038/s41590-019-0549-0
Publication status	Published - 1 Jan 2020

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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., ... Hayday, A. C. (2020). High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation. Nature Immunology, 21(1), 86-100. https://doi.org/10.1038/s41590-019-0549-0

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title = "High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation",

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 {\textquoteleft}hits{\textquoteright}, 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 {\textquoteleft}immunologic structures{\textquoteright}, 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.",

author = "Lucie Abeler-D{\"o}rner and Laing, {Adam G.} and Anna Lorenc and Ushakov, {Dmitry S.} and Simon Clare and Speak, {Anneliese O.} and Duque-Correa, {Maria A.} and White, {Jacqueline K.} and Ramiro Ramirez-Solis and Namita Saran and Bull, {Katherine R.} and Bel{\'e}n Mor{\'o}n and Jua Iwasaki and Barton, {Philippa R.} and Susana Caetano and Hng, {Keng I.} and Emma Cambridge and Simon Forman and Crockford, {Tanya L.} and Mark Griffiths and Leanne Kane and Katherine Harcourt and Cordelia Brandt and George Notley and Babalola, {Kolawole O.} and Jonathan Warren and Mason, {Jeremy C.} and Amrutha Meeniga and Karp, {Natasha A.} and David Melvin and Eleanor Cawthorne and Brian Weinrick and Albina Rahim and Sibyl Drissler and Justin Meskas and Alice Yue and Markus Lux and Song-Zhao, {George X.} and Anna Chan and {Ballesteros Reviriego}, Carmen and Johannes Abeler and Heather Wilson and Agnieszka Przemska-Kosicka and Matthew Edmans and Natasha Strevens and Markus Pasztorek and Meehan, {Terrence F.} and Fiona Powrie and Ryan Brinkman and Gordon Dougan and William Jacobs and Lloyd, {Clare M.} and Cornall, {Richard J.} and Maloy, {Kevin J.} and Grencis, {Richard K.} and Griffiths, {Gillian M.} and Adams, {David J.} and Hayday, {Adrian C.}",

year = "2020",

month = jan,

day = "1",

doi = "10.1038/s41590-019-0549-0",

language = "English",

volume = "21",

pages = "86--100",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Publishing Group",

number = "1",

}

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 2020, 'High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation', Nature Immunology, vol. 21, no. 1, pp. 86-100. https://doi.org/10.1038/s41590-019-0549-0

TY - JOUR

T1 - High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation

AU - Abeler-Dörner, Lucie

AU - Laing, Adam G.

AU - Lorenc, Anna

AU - Ushakov, Dmitry S.

AU - Clare, Simon

AU - Speak, Anneliese O.

AU - Duque-Correa, Maria A.

AU - White, Jacqueline K.

AU - Ramirez-Solis, Ramiro

AU - Saran, Namita

AU - Bull, Katherine R.

AU - Morón, Belén

AU - Iwasaki, Jua

AU - Barton, Philippa R.

AU - Caetano, Susana

AU - Hng, Keng I.

AU - Cambridge, Emma

AU - Forman, Simon

AU - Crockford, Tanya L.

AU - Griffiths, Mark

AU - Kane, Leanne

AU - Harcourt, Katherine

AU - Brandt, Cordelia

AU - Notley, George

AU - Babalola, Kolawole O.

AU - Warren, Jonathan

AU - Mason, Jeremy C.

AU - Meeniga, Amrutha

AU - Karp, Natasha A.

AU - Melvin, David

AU - Cawthorne, Eleanor

AU - Weinrick, Brian

AU - Rahim, Albina

AU - Drissler, Sibyl

AU - Meskas, Justin

AU - Yue, Alice

AU - Lux, Markus

AU - Song-Zhao, George X.

AU - Chan, Anna

AU - Ballesteros Reviriego, Carmen

AU - Abeler, Johannes

AU - Wilson, Heather

AU - Przemska-Kosicka, Agnieszka

AU - Edmans, Matthew

AU - Strevens, Natasha

AU - Pasztorek, Markus

AU - Meehan, Terrence F.

AU - Powrie, Fiona

AU - Brinkman, Ryan

AU - Dougan, Gordon

AU - Jacobs, William

AU - Lloyd, Clare M.

AU - Cornall, Richard J.

AU - Maloy, Kevin J.

AU - Grencis, Richard K.

AU - Griffiths, Gillian M.

AU - Adams, David J.

AU - Hayday, Adrian C.

PY - 2020/1/1

Y1 - 2020/1/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41590-019-0549-0

DO - 10.1038/s41590-019-0549-0

M3 - Article

C2 - 31844327

AN - SCOPUS:85076893619

SN - 1529-2908

VL - 21

SP - 86

EP - 100

JO - Nature Immunology

JF - Nature Immunology

IS - 1

ER -

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

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