Download European Research Council (ERC) funded programme of work

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