Identifying Cis-Regulatory Elements Around the ARMS2 Locus

Recent genetics studies have delineated a 23.3 Kb region around the ARMS2 locus that contains DNA sequence variants that are strongly associated with a person’s susceptibility to age-related macular degeneration (AMD). We propose to identify all of the photoreceptor-specific gene regulatory elements in this 23.3 Kb region and to test whether sequence variants within these regions found in AMD patients affect the activity of these elements. In this manner, it should be possible to determine which sequence variants are likely to cause disease, thus facilitating the genetic diagnosis of AMD.

DNA changes that can predispose patients to age-related macular degeneration (AMD) come in two varieties: those that affect sequences that encode proteins (so-called ‘coding’ changes) and those that affect sequences that control the expression of genes (‘non-coding’ changes). Although a lot is known about ‘coding’ changes, ‘non-coding’ changes are relatively poorly understood. Our research aims to develop a better understanding of the effects of ‘non-coding’ changes on a person’s susceptibility to AMD. We plan to first map the location of ‘cis-regulatory elements’ that control the expression of genes relevant to AMD. Then, we will determine which DNA changes found in AMD patients are associated with changes in the expression of these AMD genes. Once we have successfully completed this research, we should be able to more accurately diagnose AMD and predict which patients are likely to be affected by it by being able to more precisely map the effects of their DNA changes on AMD gene expression. The financial support of the BrightFocus Foundation is critical to furthering our understanding of this devastating disease.

Progress Updates

A short region of the human genome on chromosome 10 is involved in the development of age-related macular degeneration (AMD). Patients that carry certain DNA changes in this region have an increased likelihood of developing AMD. However, the specific cause of this increased risk is unknown.

Dr. Joseph Corbo and colleagues have taken a combined computational and experimental approach to study this region of chromosome 10 which contains two genes— ARMS2 and HTRA1. These researchers have identified DNA patches around these genes which control the expression of HTRA1 in certain support cells within the retina, known as Müller glia. These DNA patches are known as “cis-regulatory elements.” However, patient-associated DNA sequence or “spelling” changes in these elements did not significantly affect expression of the HTRA1 gene in customized assays. Nevertheless, Dr. Corbo’s results suggest a possible role for Müller glia in the risk for developing AMD. This finding is important because until now Müller glia cells have not been implicated in AMD despite their key structural and functional roles in the human retina.