Characterization and functional impact of somatic numtogenesis in the human cortex

This project focuses on studying nuclear mitochondrial insertions (numts), which are fragments of mitochondrial DNA that get integrated into the nuclear DNA of human cells. While this process, called numtogenesis, occurs naturally and can be passed down to future generations, it has also been observed to occur somatically in our bodies. Historically the function of numts has been difficult to study because they are repetitive and difficult to map with short read sequencing technologies, but there is emerging evidence that they can influence cell function and play a role in diseases, aging, and even complicate genetic studies. Our recent research discovered numts in the human brain’s cortex, and their presence appeared to be linked with earlier death, suggesting they may play a role in aging. However, due to limitations in the data we used, we could not fully explore the extent or impact of these insertions across different tissues or individuals. This project aims to map and study numts in more detail, especially in the human cortex, to further explore this ongoing transfer of DNA from the mitochondria to the nuclear genome and their potential to impact aging and brain function. We will accomplish this by 1) improving sequencing methods to detect numts, 2) comparing their presence across different tissues, and 3) investigating how they affect gene expression and DNA structure. By the end of the project, we aim to provide a model for how such somatic variation may occur and impact cellular function at the tissue level. Project Number: 1R01NS145291-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: RYAN MILLS (+1 co-PI) | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $602,506 | Activity Code: R01 | Study Section: Genetic Variation and Evolution Study Section[GVE] View on NIH RePORTER: https://reporter.nih.gov/project-details/11363610