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

被引：29

作者：

Abeler-Dorner, Lucie ^{[1
]}

Laing, Adam G. ^{[1
,2
]}

Lorenc, Anna ^{[1
,2
]}

Ushakov, Dmitry S. ^{[1
,2
]}

Clare, Simon ^{[3
]}

Speak, Anneliese O. ^{[3
]}

Duque-Correa, Maria A. ^{[3
]}

White, Jacqueline K. ^{[3
]}

Ramirez-Solis, Ramiro ^{[3
]}

Saran, Namita ^{[1
]}

Bull, Katherine R. ^{[4
]}

Moron, Belen ^{[5
]}

Iwasaki, Jua ^{[6
]}

Barton, Philippa R. ^{[7
]}

Caetano, Susana ^{[1
]}

Hng, Keng I. ^{[1
]}

Cambridge, Emma ^{[3
]}

Forman, Simon ^{[8
]}

Crockford, Tanya L. ^{[4
]}

Griffiths, Mark ^{[3
]}

Kane, Leanne ^{[3
]}

Harcourt, Katherine ^{[3
]}

Brandt, Cordelia ^{[3
]}

Notley, George ^{[3
]}

Babalola, Kolawole O. ^{[9
]}

Warren, Jonathan ^{[9
]}

Mason, Jeremy C. ^{[9
]}

Meeniga, Amrutha ^{[9
]}

Karp, Natasha A. ^{[10
]}

Melvin, David ^{[3
]}

Cawthorne, Eleanor ^{[4
]}

Weinrick, Brian ^{[11
]}

Rahim, Albina ^{[12
]}

Drissler, Sibyl ^{[12
]}

Meskas, Justin ^{[12
]}

Yue, Alice ^{[12
]}

Lux, Markus ^{[12
]}

Song-Zhao, George X. ^{[5
]}

Chan, Anna ^{[1
]}

Reviriego, Carmen Ballesteros ^{[3
]}

Abeler, Johannes ^{[13
]}

Wilson, Heather ^{[3
]}

Przemska-Kosicka, Agnieszka ^{[1
]}

Edmans, Matthew ^{[4
]}

Strevens, Natasha ^{[3
]}

Pasztorek, Markus ^{[1
,14
]}

Meehan, Terrence F. ^{[9
]}

Powrie, Fiona ^{[15
]}

Brinkman, Ryan ^{[12
,16
]}

Dougan, Gordon ^{[3
]}

机构：

[1] Kings Coll London, Dept Immunobiol, London, England

[2] Francis Crick Inst, London, England

[3] Wellcome Sanger Inst, Hinxton, England

[4] Univ Oxford, MRC Human Immunol Unit, Oxford, England

[5] Univ Oxford, Sir William Dunn Sch Pathol, Oxford, England

[6] Imperial Coll London, Natl Heart & Lung Inst, London, England

[7] Univ Cambridge, Cambridge Inst Med Res, Cambridge, England

[8] Univ Manchester, Fac Biol Med & Hlth, Wellcome Trust Ctr Cell Matrix Res, Lydia Becker Inst Immunol & Inflammat, Manchester, Lancs, England

[9] European Bioinformat Inst, European Mol Biol Lab, Hinxton, England

[10] AstraZeneca, R&D Biopharmaceut, Data Sci & Quantitat Biol, Discovery Sci, Cambridge, England

[11] Albert Einstein Coll Med, Dept Mol Genet, Dept Microbiol & Immunol, Bronx, NY 10467 USA

[12] British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC, Canada

[13] Univ Oxford, Dept Econ, Oxford, England

[14] Univ Appl Sci FH Campus Wien, Dept Biomed Sci, Vienna, Austria

[15] Univ Oxford, Kennedy Inst Rheumatol, Oxford, England

[16] Univ British Columbia, Dept Bioinformat, Vancouver, BC, Canada

[17] Univ Glasgow, Inst Infect Immun & Inflammat, Glasgow, Lanark, Scotland

来源：

NATURE IMMUNOLOGY | 2020年 / 21卷 / 01期

基金：

欧盟地平线“2020”; 美国国家卫生研究院; 英国惠康基金; 英国医学研究理事会; 加拿大自然科学与工程研究理事会; 加拿大健康研究院;

关键词：

GENOME-WIDE; SUSCEPTIBILITY LOCI; IDENTIFICATION; ASSOCIATION; DISEASE; BACH2; RISK; AGE; IMMUNODEFICIENCY; EPIDEMIOLOGY;

D O I：

10.1038/s41590-019-0549-0

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：86 / +

页数：19

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