High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation.,Nature Immunology

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High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation.
Nature Immunology ( IF 27.7 ) Pub Date : 2019-12-16 , DOI: 10.1038/s41590-019-0549-0
Lucie Abeler-Dörner ₁ , Adam G Laing _{1,

2} , Anna Lorenc _{1,

2} , Dmitry S Ushakov _{1,

2} , Simon Clare ₃ , Anneliese O Speak ₃ , Maria A Duque-Correa ₃ , Jacqueline K White ₃ , Ramiro Ramirez-Solis ₃ , Namita Saran ₁ , Katherine R Bull ₄ , Belén Morón ₅ , Jua Iwasaki ₆ , Philippa R Barton ₇ , Susana Caetano _{1,

3} , Keng I Hng ₁ , Emma Cambridge ₃ , Simon Forman ₈ , Tanya L Crockford ₄ , Mark Griffiths ₃ , Leanne Kane ₃ , Katherine Harcourt ₃ , Cordelia Brandt ₃ , George Notley ₃ , Kolawole O Babalola ₉ , Jonathan Warren ₉ , Jeremy C Mason ₉ , Amrutha Meeniga ₉ , Natasha A Karp ₁₀ , David Melvin ₃ , Eleanor Cawthorne ₄ , Brian Weinrick ₁₁ , Albina Rahim ₁₂ , Sibyl Drissler ₁₂ , Justin Meskas ₁₂ , Alice Yue ₁₂ , Markus Lux ₁₂ , George X Song-Zhao ₅ , Anna Chan ₁ , Carmen Ballesteros Reviriego ₃ , Johannes Abeler ₁₃ , Heather Wilson ₃ , Agnieszka Przemska-Kosicka ₁ , Matthew Edmans ₄ , Natasha Strevens ₃ , Markus Pasztorek _{1,

14} , Terrence F Meehan ₉ , Fiona Powrie ₁₅ , Ryan Brinkman _{12,

16} , Gordon Dougan ₃ , William Jacobs ₁₁ , Clare M Lloyd ₆ , Richard J Cornall ₄ , Kevin J Maloy ₁₇ , Richard K Grencis ₈ , Gillian M Griffiths ₇ , David J Adams ₃ , Adrian C Hayday _{1,

2}

Affiliation

Department of Immunobiology, King's College London, London, UK.
The Francis Crick Institute, London, UK.
Wellcome Sanger Institute, Hinxton, UK.
MRC Human Immunology Unit, University of Oxford, Oxford, UK.
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
National Heart and Lung Institute, Imperial College London, London, UK.
Cambridge Institute of Medical Research, University of Cambridge, Cambridge, UK.
Lydia Becker Institute of Immunology and Inflammation, Wellcome Trust Centre for Cell Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
European Bioinformatics Institute, European Molecular Biology Laboratory, Hinxton, UK.
Data Sciences & Quantitative Biology, Discovery Sciences, R&D Biopharmaceuticals, AstraZeneca, Cambridge, UK.
Department of Microbiology and Immunology, Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
Department of Economics, University of Oxford, Oxford, UK.
Department of Biomedical Science, University of Applied Sciences FH Campus Wien, Vienna, Austria.
The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
Department of Bioinformatics, University of British Columbia, Vancouver, BC, Canada.
Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, UK.

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.

中文翻译：

高通量表型分析揭示了免疫变异的广泛遗传和结构基础。

通过开发与高通量遗传筛查兼容的高密度小鼠免疫表型平台，我们已经确定了遗传学和结构对免疫变异的深刻贡献（http://www.immunophenotype.org）。具体来说，对 530 个独特的小鼠基因敲除进行高通量表型分析，鉴定出 140 个单基因“命中”，其中大多数以前没有免疫学关联。此外，命中的基因集中富集在人类对功能丧失的耐受性较差的基因中。免疫表型平台还暴露了密集的相关网络，将免疫参数彼此联系起来并与特定的生理特征联系起来。这种联系限制了个体免疫参数的运动自由，从而强加了基因调节的“免疫结构”，其完整性与免疫能力相关。因此，我们为理解和监测健康和疾病的免疫变异提供了扩展的遗传资源和结构视角。

更新日期：2019-12-17

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