Julian Knight group

Research overview

Our research aims to understand how genetic variation impacts genes critical to mounting an appropriate immune response and may contribute to susceptibility to infectious, inflammatory and autoimmune diseases. There is a wide spectrum of genetic variation modulating inter-individual differences in immune response with functional consequences ranging from severe primary immunodeficiency disorders to risk of multifactorial traits involving inflammation and immunity. Our recent discovery that non-coding regulatory variants are major drivers of diversity in the immune response transcriptome identifies an important mechanism for this.

The disease relevance of regulatory variants is highlighted by genome-wide association studies (GWAS) in which the majority of reported associations have been found to involve non-coding variants. To take forward the results of GWAS and translate into potential clinical benefit, we now need to define causal regulatory variants, resolve their mode of action and identify the specific modulated genes and pathways which may be therapeutic targets.

IFNB_eQTL
Local and distant associations with gene expression in human monocytes (Science 2014)

Our goal is to leverage recent advances in human genetics to improve understanding of biological process in immune disease pathogenesis, validate drug targets and advance opportunities for precision medicine.

Our work combines bioinformatics with functional genomic approaches studying genetic variants in primary cells in disease relevant contexts and establishing mechanism. This includes analysis of allele-specific gene expression, expression quantitative trait mapping and detailed characterisation of how sequence diversity modulates the epigenetic and genetic control of gene expression. 

We have established translational programmes in the genomics of sepsis as part of the Genomic Advances in Sepsis study and in ankylosing spondylitis.  

sepsis_I
Resolving heterogeneity in sepsis (Lancet Respir Med 2016)

We aim to promote use of genomics for drug target identification and validation, public engagement with genomics and implementation of genomic medicine in the clinic through education, training and a multidisciplinary team approach.

 

Podcast 'Genetic Variation in Inflammation and Immunity'

Selected recent publications

Davenport EE, Burnham KL, Radhakrishnan J, Humburg P, Hutton P, Mills TC, Rautanen A, Gordon AC, Garrard C, Hill AVS, Hinds CJ, Knight JC. 2016 Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. The Lancet Respiratory Medicine doi.org/10.1016/S2213-2600(16)00046-1 View in PubMed

van Schouwenburg PA, Davenport EE, Kienzler A-K, Marwah I, Wright B, Lucas M, Malinauskas T, Martin HC, WGS500 Consortium, Lockstone HE, Cazier J-B, Chapel HM, Knight JC*, Patel SY*. 2015 Application of whole genome and RNA sequencing to investigate the genomic landscape of common variable immunodeficiency. Clinical Immunology 160, 301-314 View in PubMed

Naranbhai V, Fletcher HA, Tanner R, O’Shea MK, McShane H, Fairfax BP, Knight JC, Hill AVS. Distinct Transcriptional and Anti-Mycobacterial Profiles of Peripheral Blood Monocytes Dependent on the Ratio of Monocytes:Lymphocytes. eBiomedicine 2, 1619–1626 View in PubMed

Naranbhai V, Fairfax BP, Makino S, Humburg P, Wong D, Ng N, Hill AVS, Knight JC. 2015 Genomic modulators of gene expression in human neutrophils. Nature Communications 6, 7545 View in PubMed

Davenport EE, Antrobus RD, Lillie PJ, Sarah Gilbert S, Knight JC. 2015 Transcriptomic profiling facilitates classification of response to influenza challenge. Journal of Molecular Medicine 93, 105-114 View in PubMed

Fairfax BP, Humburg P, Makino S, Naranbhai V, Wong D, Lau E, Jostins L, Plant K, Andrews R, McGee C and Knight JC. 2014 Innate Immune Activity Conditions Effects of Regulatory Variants upon Monocyte Gene Expression. Science 343: 1246949. doi:1246910.1241126/science.1246949 View in PubMed Hyperlink

Knight JC. 2014 Strategic approaches to establishing function for regulatory genetic variants involved in disease. Genome Medicine 6, 92 View in PubMed

Wong D, Lee W, Humburg P, Makino S, Lau E, Naranbhai V, Fairfax BP, Chan K, Plant K, Knight JC. 2014 Epigenomic profiling of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach. Genome Biology 15, 494 View in PubMed

Fairfax BP and Knight JC. 2014 Genetics of gene expression in immunity to infection. Current Opinion in Immunology 30, 63-71 View in PubMed

Plant K, Fairfax BP, Makino S, Vandiedonck C, Radhakrishnan J,  Knight JC. 2013 Fine mapping genetic determinants of the highly variably expressed MHC gene ZFP57. European Journal of Human Genetics doi:10.1038/ejhg.2013.244 View in PubMed

Trowsdale J & Knight JC. 2013 Major Histocompatibility Complex Genomics and Human Disease. Annual Review of Genomics and Human Genetics 14, 301-323 View in PubMed

Fairfax BP, Makino S, Radhakrishnan J, Plant K, Leslie S, Dilthey A, Ellis P, Langford C, Vannberg FO, and Knight JC. 2012 Genetics of gene expression in primary immune cells identifies cell type–specific master regulators and roles of HLA alleles. Nature Genetics 44, 502-510 View in PubMed

Vandiedonck C, Taylor MS, Lockstone H, Plant K, Taylor JM, Durrant C, Brockholme J, Fairfax BP, Knight JC. 2011 Pervasive haplotypic variation in the spliceo-transcriptome of the human Major Histocompatibility Complex. Genome Research 21, 1042 View in PubMed

Knight JC. 2009. Human Genetic Diversity. Functional Consequences for Health and Disease. Oxford, Oxford University Press. Link

Funding sources

Wellcome Trust, Arthritis Research UK, Psoriasis Society, Oxford Biomedical Research Centre

Research area

Genomics of immunity and inflammation

Keywords

Keywords: Gene expression, regulatory variants, genome editing, MHC, immunity, inflammation, sepsis, transcription, single nucleotide polymorphism, ankylosing spondylitis, eQTL, functional genomics, epigenomics, drug targets