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Understanding our individual immune response Professor Julian Knight group, Wellcome Trust Centre for Human Genetics, University of Oxford Our Group is located in the Wellcome Trust Centre for Human Genetics at the University of Oxford. We use genetics to understand the individual immune response and how this may relate to disease. Genetic association studies of disease susceptibility Understand the functional basis of these genetic associations Coding variants altering protein structure Identify new processes involved in causing disease Noncoding DNA variants altering gene regulation: important to identify modulated gene/pathway Define potential new drug targets Allow better use of existing drugs Working towards a cure ERC funding has supported RegVarMHC: a 5 year project investigating genetic and epigenetic determinants of allele-specific gene expression in the MHC Aim: to determine the functional consequences of genetic variation associated with risk of developing autoimmune, infectious and inflammatory disease. The work focused on the Major Histocompatibility Complex (MHC), a highly polymorphic region of the genome that shows striking disease associations but the specific genetic variants and genes responsible for these associations remain unresolved. Hypothesis: disease-associated variants modulate gene expression within the MHC and genome-wide. Findings The study was conducted over 5 years at the University of Oxford. We advanced understanding of the nature of genetic variation in the MHC, how it may modulate gene expression and the consequences of this for disease. We demonstrated the importance of context-specificity in the action of regulatory genetic variants and produced route maps of putative functional variants and their modulated genes for different immune cell types and activation states relevant to innate immunity. We discovered new functional variants, for example involving the MHC master regulator CIITA and the gene ZFP57 involved in imprinting. We developed new open access bioinformatics tools for analysing functional genomic data and allele-specific gene expression in the MHC. We are applying these approaches in the context of autoimmune and infectious disease. •Fairfax BP, Makino S, Radhakrishnan J, Plant K, Leslie S, Dilthey A, Ellis P, Langford C, Vannberg FO, Knight JC. 2012 Genetics of gene expression in primary immune cells identifies cell-specific master regulators and roles of HLA alleles. Nature Genetics 44, 502-510 •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 •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. •Plant K, Fairfax BP, Makino S, Vandiedonck C, Radhakrishnan J, Knight JC. 2014 Fine mapping genetic determinants of the highly variably expressed MHC gene ZFP57. European Journal of Human Genetics 22, 568–571. •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 •Fang H, Knezevic B, Burnham KL, Knight JC. 2016 XGR software for enhanced interpretation of genomic summary data, illustrated by application to immunological traits. Genome Medicine 8, 129 •Neville MJ, Lee W, Humburg P, Wong D, Barnardo M, Karpe F, Knight JC. 2017 High resolution HLA haplotyping by imputation for a British population bioresource. Human Immunology doi: 10.1016/j.humimm.2017.01.006 Magnetic microbeads are used to capture specific white cell populations Regulatory variants are context specific, dependent on cell type and state of activation Unstimulated 2h LPS RNA fluorescence in situ hybridisation for LTA 24h LPS Most GWAS arise due to regulatory variants altering gene expression. They may act locally or at a distance. New sequencing technologies define allele-specific gene expression Regulatory variants can affect many different mechanisms of gene regulation