Identification and predictive functional classification of cryptic exon usage in Amyotrophic Lateral Sclerosis

Key information

Application close date
07 February 2023, 11:59 GMT
Hours per week
36 (full time)
Application guidance
Posted 22 December 2022

Research topics

Computational & Systems Biology Gene Expression Genetics & Genomics Neurosciences
Background texture taken from the lab imagery.

This is a summer student position supervised by Koustav Pal from Rickie Patani's lab. 

Introduction to the Science

Amyotrophic Lateral Sclerosis (ALS), or Lou Gehrig’s disease, is an incurable, progressively debilitating neurodegenerative disorder, in which mislocalisation of RNAs from their physiological locale (synapse, axon, cytoplasm, nucleus) is commonly observed. A key protein required for the transport and proper localisation of RNA is TDP-43/TARDBP, and TDP-43 mutations are causatively linked to ALS and our lab has shown that TDP-43 itself is mislocalised in ALS motor neurons (Hall et al. 2017). TDP-43 is also known to be a splicing regulator and affects defective alternative splicing events (dASe) in ALS-associated genes (Rosa Ma et al. 2022). However, we question the frequency of these dASe, and the functional context within which TDP-43 affects dASe.

Towards this aim, we aim to:

  • Use existing next-generation RNA sequencing transcriptomics datasets from iPSC (induced pluripotent stem cell)-derived motor neurons and astrocytes to identify dASe events.
  • Next, we will use RNA binding sequencing datasets to predict RNA binding motifs of a large set of RNA binding proteins in dASe. Next, we will use correlation matrices and clustering procedures to understand the RBP context influencing TDP-43 binding.
  • Finally, we will study the differential activity of dASe events between motor neurons and astrocytes.

 

About the Project

This project is a purely analytical project involving the usage of various bioinformatics tools and pipelines to process massive amounts of data. Downstream statistical analysis will be done using R and markdown documents. The project will involve the usage of Crick’s High-performance computing (HPC) cluster via job scheduling services.

 

About You

This project involves a large amount of day-to-day programming and is suitable for, but not limited to, an analytically minded individual with a quantitative background (biostatistics, statistics, mathematics, physics, computer sciences). Individuals majoring in biological sciences with a minor quantitative background are also encouraged to apply.

 

References

1.         Hall, C.E., Yao, Z., Choi, M., Tyzack, G.E., Serio, A., Luisier, R., . . . Patani, R. (2017)

            Progressive motor neuron pathology and the role of astrocytes in a human stem cell model of VCP-related ALS.

            Cell Reports 19: 1739-1749. PubMed abstract

2.         Ma, X.R., Prudencio, M., Koike, Y., Vatsavayai, S.C., Kim, G., Harbinski, F., . . . Gitler, A.D. (2022)

            TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A.

            Nature 603: 124-130. PubMed abstract