An in depth look at the sequence and phylogeny of the HLA class II genes & Identifying regulatory factors altering HLA class II allelic expression levels

An in depth look at the sequence and phylogeny of the HLA class II genes & Identifying regulatory factors altering HLA class II allelic expression levels

Associated Students: 
Email Address: 
214513008@stu.ukzn.ac.za
Phone Number: 
+27 81 770 0029
Supervisor(s): 

Muthen's current research focus is in the field of human genetics concentrating on the human leukocyte antigen (HLA) genes which have been identified as the region with the most associations to viral, bacterial and autoimmune diseases.

The human leukocyte antigen (HLA) region has the highest number of disease associations as demonstrated by genome wide association studies (GWAS). This region also has the highest percentage of mutations compared to the rest of the genome combined. The proteins encoded by the various HLA genes play a major role in the immune response by presenting self and foreign peptides to cells of the immune system such as your CD4+ and CD8+ T lymphocytes. Many diseases such as HIV, Chron’s disease, Multiple Sclerosis, Systemic Lupus Erythematosus have been linked to specific HLA genes and mutations, however, the mechanisms contributing to these diseases have not been fully understood. Several recent studies have also shown that allele specific expression of certain HLA genes determines disease outcomes in HIV, Chron’s disease, Hepatitis B (HBV) and Graft Versus Host disease (GvHD). Most studies thus far have looked at the variable expression of the HLA class I genes, however, not much work has been done on the class II region. Our current research approach is novel and will focus on the HLA class II genes. We will look at a 2000 base pair region upstream of transcription start site as well as the protein coding gene region to determine how the sequences have evolved over time. We have identified several mutations within the core promoter region and beyond which we expect to play a role in the regulation of expression of the class II genes. We plan to use chromosome immunoprecipitation techniques to determine whether these mutations do play a role in transcription and are indeed located within transcription factor binding sites. Thereafter we will alter the gene to determine what effects this has on the allelic expression of class II genes.

Identifying the mechanisms that regulate expression will perhaps provide insight into the mechanisms associating the HLA region with various diseases. Furthermore, it will allow us to manipulate these processes and provide therapeutic interventions.