Bedrosian Lab
The brain is a genetic mosaic. Individual neurons harbor unique genotypes distinct from one another and distinct from the individual’s inherited genetic code. This phenomenon is attributed to mutations that arise in neural progenitors during prenatal development, a time of rapid proliferation that peaks at more than 100,000 cell divisions per minute. The result is a mosaic brain where cells are defined by a signature of single nucleotide variants, copy number variation and retrotransposon insertions. Each somatic variant has the potential to influence the function of its host cell and the wider neuronal network. To some extent, brain mosaicism likely contributes to normal neuronal diversity and complexity. But brain mosaicism has also been linked to disorders ranging from structural brain abnormalities to epilepsy and psychiatric disease.
The Bedrosian Lab is interested in genetic mechanisms that shape the developing brain and contribute to neurodevelopmental disease. Its team uses a translational approach that combines characterization of patient brain specimens with functional modeling in patient-derived cell lines and transgenic mice. The Bedrosian Lab’s work addresses fundamental questions related to how genetic mosaicism affects neurodevelopment during health and disease, such as how somatic mutations arise and populate the brain, how they affect individual cells and the larger network/structure, how a small number of affected cells have a widespread effect and how somatic mutations contribute to complex phenotypes.
Areas of Research
The Bedrosian Lab uses single-cell RNA-sequencing of surgically resected patient brain specimens to identify affected cell lineages in pediatric patients with brain malformations caused by somatic mutations. This analysis allows researchers to reconstruct the developmental history of patients’ somatic variation and to learn how their diseases arose. Identifying patterns in the types of affected cells will eventually help researchers understand what kinds of cells to target with therapeutics.
Some pediatric brain tumors coincide with epilepsy to a high degree. The Bedrosian Lab uses spatial proteomic analysis of patient tumor tissue to study how somatic mutations affect specific cell types in different ways. This research helps identify why some tumors often contain epileptogenic cells.
To study the function of particular somatic variants in brain development, the Bedrosian Lab induce brain mosaicism by genetic manipulation of various model systems, including human cerebral organoids and developing mice in utero. The team uses a fluorescent tag to mark mosaic cells and observes how the somatic mutations disrupt the maturation of those cells. By directly testing the function of somatic variants in brain development, researchers can identify molecular targets for future therapies and test potential treatments.
Nearly half of the human genome is derived from transposable elements (TEs) — mobile genetic elements that replicate and insert copies of themselves throughout the genome. TEs generate brain mosaicism that has been associated with a number of neurological diseases. We use genetic techniques to investigate how TEs contribute to brain development in various contexts.
