Approved Research

Identifying non-coding regulatory variants associated with mature B cell neoplasms and B cell mediated autoimmune diseases.

Lay summary

All cells in the human body have same genetic blueprint yet have diverged to produce different proteins and perform distinct functions. This cellular diversity is achieved through regulation of gene expression, ensuring each cell switches on the right genes at the right time. As cells differentiate, non-coding regions of deoxyribonucleic acid (DNA), called cis-regulatory elements, exercise strict control over gene expression. However, mutations in regulatory DNA can alter the genes expressed by a cell and lead to disease. As the non-coding genome makes up ~99% of DNA, most genetic variants which have been linked to disease do not affect genes themselves, but instead are hypothesised to underpin disease through altering gene expression.

B cells are essential to the immune response, recognising foreign antigens and differentiating into to plasma cells, which producing large quantities of antibodies specific to the invading antigen. Using genome sequencing datasets from B and plasma cells, we have identified thousands of cis-regulatory elements which regulate the expression of genes crucial to B cell differentiation. This project aims to understand how genetic variants in regulatory DNA, may alter gene expression in B cells and contribute to disease.

To answer this question, we aim to first identify genetic variants associated with susceptibility towards cancers of B cells (including types of Lymphoma, Leukaemia and Myeloma) and autoimmune diseases, in which B cells produce antibodies which target parts of the human body. Following this we aim to map disease-associated variants located outside of genes to previously identified cis-regulatory elements, to understand how variants may underlie disease through disrupting gene expression in B cell differentiation.

We intend that this project will be completed by September 2023 and will result in associating novel genes and molecular mechanisms with diseases of B cells. We hope to impact public health through identifying targets for future biomedical research and contributing towards scientific understanding of the molecular basis of disease.