“Long-Read Functional Genomics as a Tool for Precision Medicine: Insights into Genetic Variation and Disease Susceptibility”
Jasmine Sakr
The structure of the genome encompasses not only the DNA sequence, which includes regulatory elements, repeats, and CpG islands, but also its three-dimensional organization, such as regions of open chromatin, and epigenetic modifications. Epigenetic mechanisms that modify DNA and histone tails using methylation or other modifications without changing the underlying nucleotide sequence play a crucial role in the control of gene activity. The specific location of these modifications offer key insights into cellular differentiation, development, and are also implicated in the progression of various diseases. Together, these factors contribute to the complex regulation of genes and their expression. Investigating genetic variation through genome structure and epigenetics provides valuable insights into the regulation of gene expression.
My thesis investigates genetic variation and epigenetics using long-read sequencing on the Oxford Nanopore platform in mouse and human samples. First I characterize genome-wide epigenetic effects of heterochromatin disruption at the disease locus of facioscapulohumeral muscular dystrophy (FSHD), which is caused by a combination of structural variation in repeats and/or hypomethylation at the disease locus. Next I use Fiber-seq to profile open chromatin regions in the brain of two mouse strains and explore variation in a genotype-specific manner. Lastly, I calculate transcription and decay rates of transcript isoforms during myogenesis in the C2C12 skeletal muscle cell line. Together, these projects contribute to a deeper understanding of the complexity of gene regulation in health and disease.
