Research Interests of the Julian Knight Group
As human beings we are unique, shaped by our environment and life experiences but also by our genetic make-up. Human genetic diversity is associated with phenotypic variation, notably in our physical characteristics but also in determining our susceptibility and response to disease, often as part of a multi-factorial disease process.
The commonest form of genetic diversity are single nucleotide differences, a spelling change in the DNA code where one nucleotide is replaced by another but other larger structural variants are also being identified. The challenge amidst so much genetic variation - there are over 10 million single nucleotide differences alone among humans - is to define specific variants responsible for common multi-factorial diseases such as infections, diabetes or heart disease. There have been major advances in how we define the genetic determinants of common disease over the last few years based on using many hundreds of thousands of genetic markers across the genome to look for association with disease in 'genome-wide association studies' but a major challenge remains once a region of the genome has been implicated in disease to then define the specific functionally important causative variants.
The work of our group aims to complement these population genetic approaches by functional studies to define causative variants, particularly those variants which affect how our genes are switched on and the levels of gene expression regulated. These 'non-coding DNA' regulatory variants are very important in common diseases and we have developed a number of methods to try and identify them using both model experimental systems and analysis of circulating white blood cells from patients.
Our clinical interest is in infectious and autoimmune diseases such as sepsis and inflammaotry arthritis with patient recruitment through a number of clinical collaborators. The main gene region we work on is called the Major Histocompatibility Complex on chromosome 6 which is a remarkable part of the human genome, it is more polymorphic and gene dense than any other region, and shows more associations with autoimmune and infectious diseases than anywhere else studied to date.