1 PhD project offered in the IPP winter call 2020/2021
Aneuploidy and haploinsufficiency are two forms of gene-dosage alteration, where transcriptional and cellular changes ultimately result in a diseased state. However, gene and whole chromosome duplications are a major driver for the evolution of novel traits, for example in the vertebrate brain. Cells are equipped with control systems to ensure appropriate regulation of gene copies that allow gene diversification and expression control.
PhD Project: Gene paralogues in neuronal splicing regulation
In this project, the PhD student will work on two paralogous genes, whose protein products are a component of a supramolecular RNA‑protein complex, the spliceosome. Although the gene duplication event occurred more than 90 mya, the protein product remained almost identical, while displaying a tissue-specific expression pattern. Interestingly, the mutations in each of the two paralogues lead to very distinct developmental disorders in humans. It remains unclear, whether and how the two paralogues regulate the activity of the spliceosome and how this would impact the disease outcome.
The aim of the PhD project will be to dissect the intrinsic and extrinsic difference in these genes and products using both biochemical and in vivo assays. The PhD candidate will use CRISPR engineering in stem cell and neuronal cultures, as well as brain cortex organoids to model the tissue specific contribution of these splicing regulatory factors. Using live imaging, multi-omics, CLIP as well as biochemical assays, we will dissect the dependencies contributing to the distinct biology of these genes and their gene products.
We are looking for a PhD student with a strong interest in mechanisms of gene regulation and developmental cell biology. Your enthusiasm to work at the bench is driven by a biomedical mindset and the curiosity to unravel disease mechanisms. If you are a teamplayer and show a high degree of motivation and excitement for science, you will be the right person to join our group.
Publications relevant to this project
Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, Collins RL et al. (2020) The Mutational Constraint Spectrum Quantified from Variation in 141,456 Humans. Nature, 581(7809):434–43.
Keller Valsecchi CI*, Basilicata MF*, Georgiev P, Gaub A, Seyfferth J, Kulkarni T, Panhale A, Semplicio G, Manjunath V, Holz H, Dasmeh P and Akhtar A (2020) RNA nucleation by MSL2 induces selective X chromosome compartmentalization. Nature, doi: 10.1038/s41586-020-2935-z
Deciphering Developmental Disorders, Study (2017) Prevalence and Architecture of de Novo Mutations in Developmental Disorders. Nature, 542(7642):433–38.
Basilicata MF, Bruel AL, Semplicio G, Keller Valsecchi CI, Aktaş T, Duffourd Y, Rumpf T et al. (2018) De Novo Mutations in MSL3 Cause an X-Linked Syndrome Marked by Impaired Histone H4 Lysine 16 Acetylation. Nature Genetics,50(10):1442–51.
Keller Valsecchi CI, Basilicata MF, Semplicio G, Georgiev P, Gutierrez NM, Akhtar A (2018) Facultative Dosage Compensation of Developmental Genes on Autosomes in Drosophila and Mouse Embryonic Stem Cells. Nature Communications, 9(1): 3626.