RNA-Seq profile of the Drosophila model of Spinal Muscular Atrophy
Spinal Muscular Atrophy (SMA) is a devastating neurodegenerative disorder that represents the second most common cause of hereditary infant death. The disease is caused by the reduced expression of the ubiquitous protein SMN (Survival of Motor Neuron), which is known to have a central function in the assembly of ribonucleoprotein complexes involved in pre-mRNA splicing. More recently, this protein has been reported to be involved in trafficking of mRNA molecules along neuron axons. Although the SMA causing gene has been identified for over a decade, the exact mechanisms that lead to the specific death of motor neurons remain unclear. A long-standing hypothesis suggests that the disease emerges from motor-neuron specific changes in pre-mRNA splicing that affect key genes required the survival of these cells. However, such genes have never been identified. Recently, the group of Prof. Artavanis-Tsakonas (Harvard Medical School) has developed Drosophila models of SMA that recapitulate several of the human disease characteristics and have provided a powerful genetic model to identify genes that can modify the disease phenotype, several of which are involved in pre-mRNA splicing processes (Chang et al 2008; Sen et al 2011). Together with the group of Dr. David van Vactor (Harvard Medical School), we now aim to take advantage of these models to identify SMA-dependent changes in pre-mRNA splicing by using next generation sequencing approaches.
The present project involves the use of RNA-seq libraries of normal and mutant (SMA) flies to search for differential gene expression and, in particular, variations in alternative splicing ratios or presence of aberrant splice site choices. The sequence context of aberrantly spliced mRNAs will be analyzed for signature motifs in order to provide insights into the molecular basis of SMN-dependent splicing defects. Finally, a comparative analysis between Drosophila genes displaying altered splicing and the homologous human genes will be performed, in search for potentially conserved targets of SMN-dependent splicing.
Candidate requirements: MSc level bioinformatics student
Duration: 4-6 months
Supervisors:
Dr. Andreia Amaral (andreia.fonseca@gmail.com)
Prof. Margarida Gama-Carvalho (mhcarvalho@fc.ul.pt)
BioFIG – FCUL
Open: January 10 2012 (until filled)
