Julian Knight Group
Research Projects
Our work aims to understand how genetic variation between individuals modulates genes critical to mounting an appropriate immune and inflammatory response, and so contributes to susceptibility to infectious and autoimmune diseases. Serological typing, linkage and genome-wide association studies (GWAS) have defined many gene loci associated with such diseases while rare highly penetrant mutations have also been resolved. A significant roadblock in the field remains however in terms of defining specific causal variants and their mode of action in the disease setting, notably in the context of loci identified from genetic association studies.
To address this question we have adopted a functional genomic approaches that seeks to map regulatory variants based on a combination of high throughput profiling of transcription and sequence variation together with detailed molecular characterization of specific variants and gene loci. Our work is collaborative, seeking to compliment and inform the work of disease specific groups and clinicians while also working with colleagues in genomics, bioinformatics and statistical genetics to capitalize on current advances in next generation sequencing and its application in functional genomics.
Current research efforts are focused on the following areas:
1. Genetic and epigenetic determinants of disease involving the major histocompatibility complex (MHC).
The MHC on chromosome 6p21 is a remarkably polymorphic region strongly associated with susceptibility to autoimmune, infectious and other diseases but the causal functionally important variants remain largely unknown. The identification of specific disease risk variants is particularly challenging in the MHC due to the extent of genetic diversity, the complexity of coinheritance between genetic markers and the difficulty of resolving specific regulatory variants modulating gene expression. We have previously established the importance of allele-specific gene expression in the MHC at specific loci including the TNF, LTA, HSP70, ZFP57 and HLA-DRB1 genes. We have complimented this by recent work defining allelic differences in transcription for specific extended HLA haplotypes associated with disease. The functional genomics of the MHC remains a major focus of the lab as we seek to define at a locus-wide level the relationship between genetic variation in the MHC and modulation of gene expression in both health and disease.
2. Mapping genetic modulators of innate and adaptive immunity.
Recent GWAS have highlighted the extent of association for autoimmune, infectious and inflammatory diseases in non-MHC loci and we seek to map regulatory variants modulating gene expression in a variety of cellular contexts relevant to disease. We have analysed gene expression as a quantitative trait in different primary immune cell populations and demonstrated that a high degree of cellular specificity exists. We have used this data to help resolve regulatory variants from GWAS signals. Our work has also studied specific cytokines such as IL6 and important pathophysiological states such as endotoxin tolerance, vitamin D stimulation and heat shock to resolve important underlying functionally important genetic variation. We are extending this work to different contexts and particular environmental modulators of disease risk such as vitamin D or endotoxin.
3. Defining causal variants in a disease context.
We compliment our work using model systems and analysis of cells from healthy volunteers with patient focused collaborative studies involving clinical samples. This includes a major focus on autoimmune disease (GENExpressID study) together with common and rare causes of severe infection. We work with Professor Charles Hinds, Professor Adrian Hill and the GAinS Investigators to use functional genomic approaches to define regulatory variants modulating gene expression in patients with severe sepsis admitted to intensive care. Other collaborative work involves bacterial and mycobacterial infection with Professor Adrian Hill, Dr Stephen Chapman and colleagues. We compliment this analysis of common infectious diseases by work with Dr Smita Patel, Professor Helen Chapel and colleagues in Clinical Immunology to understand the causes of rare primary immunodeficiency disorders.
4. Innovative approaches to resolving regulatory variants.
We are interested in using contemporary approaches in genomics and molecular genetics to advance our ability to identify and characterise functionally important genetic variation. An important approach involves defining allele-specific gene expression both at the transcript level and based on recruitment of RNA polymerase and specific transcription factors using haplotype-specific chromatin immunoprecipitation (haploChIP) that was developed in the lab. Current efforts involve using next generation sequencing technology to understand allele-specific gene expression in a high throughput setting.
Keywords: Gene expression, regulatory variants, major histocompatibility, MHC, immunity, inflammation, sepsis, multiple sclerosis, transcription, single nucleotide polymorphism, tumour necrosis factor
This project is sponsored by the Wellcome Trust, Medical Research Council, European Research Council and the Multiple Sclerosis Society
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