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Dissecting the function and molecular evolution of long non-coding RNAs

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  • Full or part time
    Dr J Aspden
    Dr M. O'Connell
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Background:

Protein-coding genes make up only ~4% of the human genome. While we have limited understanding of the function of the remaining ~96% of genomic sequence, extensive RNA-Seq has revealed that ~85% of the genome is in fact transcribed. The majority of these transcripts are long non-coding RNAs (lncRNAs). Current estimates for the number of lncRNAs that are transcribed is 6,000-10,000 for human and ~2,000 for Drosophila. LncRNAs exhibit far more tissue and developmental stage specific expression than mRNAs, and they are particularly enriched in the nervous system and testes. Recent focus has been on the role of lncRNAs in transcriptional regulation, however most lncRNAs are present in the cytoplasm and many are enriched there with respect to the nucleus. The mechanistic action of cytoplasmic lncRNAs is beginning to be elucidated and we are particularly interested in those interacting with the translational machinery, i.e. ribosomes; either to regulate translation or to be translated themselves. Ribo-Seq has revealed translation ~50% of lncRNAs in mouse embryonic stem cells and ~34% in Drosophila. These translation events on lncRNAs remain controversial. Ribo-seq data has also provided support to the hypothesis that lncRNAs represent a point in the process of evolving new protein-coding genes from non-coding DNA.

In general, lncRNAs are poorly conserved across species with only 6% of zebrafish lncRNAs conserved in human and mouse. However, estimates of orthology vary widely, e.g. 12% of human lncRNAs have direct homologs across the vertebrates while 30% of human lncRNAs are primate-specific. Brain expressed lncRNAs are the most highly conserved population of lncRNAs. Unsurprisingly, lncRNAs diverge far more rapidly than protein-coding sequences.

We are interested in assessing how the functional elements of lncRNAs evolve and how RNA structures and protein-binding sites contribute to the evolution of novel protein-coding elements derived from lncRNAs.

Objectives
This project is an exciting opportunity to computationally dissect the sequence signatures/patterns, functional elements and evolutionary conservation of lncRNAs in the cytoplasm of both Drosophila melanogaster and mammals (including human neurons).

1) To identify sequence and structural motifs that contribute to lncRNA function (including potential RNA-binding protein interactions).
2) Use Ribo-Seq and RNA-Seq data sets (novel and published) to understand the translation potential of lncRNAs.
3) To determine the relationship between conservation and evolution of novel protein coding genes through lncRNAs as a mechanism of novel gene genesis.

Novelity and Timeliness
Our understanding of lncRNAs has transformed over the last 5 years. We now have the exciting opportunity to make use of ribosome profiling across a number of species to dissect cytoplasmic lncRNA function and evolution. Using computational analysis of lncRNAs in both humans (and rodents) and Drosophila melanogaster this project has the potential to provide key insights into lncRNA genes and their contribution to human health.

Approaches you will learn and use:
-Ribo-Seq and RNA-Seq analysis tools and programs.
-Evolutionary conservation analysis amongst mammals and Drosophila
-Motif, structural prediction and incorporation of additional experiments data outputs.
-script writing – UNIX and programming in Python
-R

You will also have the opportunity to develop new tools and metrics to study probe cytoplasmic function and evolution.

This is an exciting collaboration between RNA biologist Aspden and molecular evolution expert O’Connell. lncRNA Ribo-Seq data will be assessed using Next Generation Sequencing methods taking advantage of training etc within LeedsOmics (http://www.leedsomics.org/).

Further further information on Aspden and O’Connell Groups:
http://aspdenlab.weebly.com
http://mol-evol.org

Funding Notes

Project is eligible for funding under the FBS Faculty Studentships scheme. Successful candidates will receive a PhD studentship for 4 years, covering fees at UK/EU level and stipend at research council level (£14,777 for 2018-19).

Candidates should have, or be expecting, a 2.1 or above at undergraduate level in a relevant field.
If English is not your first language, you will also be required to meet our language entry requirements.
The PhD is to start in Oct 2018.

Please apply online here https://studentservices.leeds.ac.uk/pls/banprod/bwskalog_uol.P_DispLoginNon
Include project title and supervisor name, and upload a CV and transcripts.

References

Aspden, J. L., Eyre-Walker, Y. C., Philips, R., Amin, U., Mumtaz, A. S., Brocard, M., Couso, J. P. Extensive translation of small ORFs revealed by Poly-Ribo-Seq. eLife 10.7554/eLife.03528 (2014).

Hellsten, U. , Aspden, J. L. , Rio, D. C. & Rokhsar, D. S. A segmental genomic duplication generates a functional intron. Nature Communications 2, 454 (2011).

Morgan CC, Foster PG, Webb AE, Pisani D, McInerney JO and O’Connell MJ* (2013) Heterogeneous models place the root of the placental mammal phylogeny. Molecular Biology and Evolution. doi: 10.1093/molbev/mst11

Webb AE, Gerek ZN, Morgan CC, Walsh AT, Loscher CE, Edwards SV, O’Connell MJ* (2015) Adaptive Evolution as a predictor of species-specific innate immune response. Molecular Biology and Evolution.

How good is research at University of Leeds in Biological Sciences?

FTE Category A staff submitted: 60.90

Research output data provided by the Research Excellence Framework (REF)

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