Presentation description

Huntington's disease (HD) is a rare autosomal dominant neurodegenerative disease caused by the somatic expansion of a CAG short tandem repeat (STR) in the huntingtin gene. HD manifests as a wide variety of cognitive, motor, and psychological symptoms, but its most notable symptoms are undesired muscle spasms known as chorea. Throughout the lifetime of individuals who inherit an allele with 39 or more CAG repeats, the repeats steadily expand, producing a huntingtin protein with an expanded polyglutamine sequence that is toxic to neurons. Thus, suppressing this somatic instability could be key in preventing and treating HD. We are collaboratively investigating emerging HD treatments in a HD mouse model. This effort is also exploring the use of long-read sequencing as a more economical and accurate method to quantify repeat instability from sample tissues both before and after treatment. As a pilot study to evaluate long-read sequencing for measuring repeat instability, we extracted DNA sequences spanning the HD locus from six HD samples plus 31 controls and determined the number of CAG repeats present in each read. Using a Gaussian mixture model, we phased each read, segregating them into groups characterized by the probability they arose from an expanded pathogenic allele or an unexpanded nonpathogenic allele. Our method for quantifying somatic instability can be immediately applied to mouse data to assist in developing a treatment for HD and can be further used to detect instability at other disease-associated STR loci.