Alasdair Mackenzie

The ENCODE consortium have recently shown that the vast majority of the information in the human genome required to maintain health is not contained in genes. In addition, it has been shown that up to 95% of the genetic differences that have been associated with disease are found outside of genes.

We are interested in finding out how these genetic differences, also known as polymorphisms, within the human genome can change where, when and by how much neuropeptide genes are activated within the human nervous system. We are particularly interested in the role of gene mis-expression in generating susceptibility to conditions that include depression, obesity, addiction and inflammatory diseases such as arthritis.

To this end we have used comparative genomics to identify the genetic "switches" or cis-regulatory regions that control the expression of a number of different genes including substance-P, Brain derived neurotrophic factor (BDNF), the Cannabinoid-1 receptor gene, (CB1) and the galanin gene (GAL) that all play a role in controlling appetite, mood and inflammatory pain.

We have also learned how to manipulate the activity of these cis-regulatory regions and to test the effects of polymorphic variation in transgenic lines and cell lines using a number of different drug treatments. Our studies have shown that disease associated polymorphisms occur in cis-regulatory regions and alter cell specific levels of activity and responses to specific drugs.

Recently we have made a major breakhrough in our use of CAS9/CRISPr technology which has allowed us to selectively knock out these cis-regulatory regions within mice within a matter of weeks and at comparitively little expense. Behavioural and transcriptional analysis of these mouse lines has shown that, not only are these highly conserved sequences critical to normal gene expression, but that their deletion has significant effects on the fat and alcohol intake and anxiety in these mice in a manner that suggest their critical role in health and why they have been conserved through evolution.

In addition to understanding the basis of disease these novel observations hold the key to understanding why some patients fail to respond to certain drug therapies or suffer dangerous side effects. We believe that only by understanding how genetic differences within the human genome lead to disease and differences in drug response can we deliver on the promises of personalised medicine.

Recent studies have shown that epigenetic changes in the form of DNA-methylation also have a major effect on gene regulation by altering the function of promotors and enhancer regions. Levels of methylation at enhancer sequences is affected by environmental events such as early life stress or poor diet. Thus, exploring the effects of epigenetic changes on the functioning of enhancers and promoters represents the next big step our lab is set to take in understanding the interaction of environment and genetics in disease.