Posted By: The American Journal of Human Genetics, AJHG
Each month, the editors of The American Journal of Human Genetics interview an author of a recently published paper. This month, we check in with Thorkild (@thorkildterkelsen.bsky.social) to discuss his recent paper “Position effect at the SOX3 locus by an interchromosomal insertion causes hereditary spastic paraplegia.“
AJHG: What motivated you to start working on this project?
TT: This project started with a family affected by a rare X-linked recessive neurological disease where a genetic diagnosis had been pursued for many years. When I joined the project, the disease had recently been linked to an interchromosomal insertion in an intergenic region of the X chromosome, but it was unclear how the insertion could cause disease, as no genes appeared to be directly affected. I was intrigued by this question, which motivated me to pursue a PhD in functional genomics and work on this project.
AJHG: What about the paper/project most excites you?
TT: What fascinates me most is that different insertions at the same locus can lead to such a wide range of phenotypes, from disorders of hair growth to retinal disease, hereditary spastic paraplegia, and polyneuropathy. Even though the Xq27.1 locus has been studied for many years, considerable uncertainty remains about the mechanisms underlying this pleiotropy. Seeing multiple approaches like Hi-C, transcriptomics, neural differentiation of iPSCs, and CRISPR perturbations converge on the same disease mechanism in hereditary spastic paraplegia was especially exciting.
AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?
TT: Our study illustrates how a genetic variant can cause disease through effects on genome organization and highlights that predicting the clinical impact of non-coding variants remains challenging, despite significant advances in our ability to detect them. Our work also demonstrates the value of analyzing iPSCs derived from patient cells to investigate disease mechanisms in these situations.
AJHG: What advice do you have for trainees/young scientists?
TT: Planning experiments carefully and thinking through the limitations of the experimental design well before starting the actual experiments are essential for obtaining meaningful results. Bumps along the way are inevitable, but things usually work out in the end.
AJHG: And for fun, tell us something about your life outside of the lab.
TT: I am the proud father of two wonderful children who keep me busy when I am not in the lab or at the hospital. I also enjoy playing music or going for a run. There are many good places to go in the city I live in, including nice beaches and green areas close to the campus.
Thorkild Terkelsen, PhD, is a Postdoc and Clinical Associate Professor at Aarhus University.