Project proposal details

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Project title
Evolutionary genomic analysis of Tissue Factor gene 3’ untranslated region in primates and human populations
Contact name
Matteo Fumagalli
Project based at
Silwood Park (Imperial)
Project description
Tissue Factor (Coagulation Factor III) is a cell surface glycoprotein that initiates blood coagulation, as well as serving other functions involved in cell biology. Fine control of Tissue Factor expression is critically important, as on the one hand it is needed to stop bleeding after vascular injury, but on the other hand it can stimulate intra-vascular thrombosis in cardiovascular disease and cancer. Tissue Factor expression is regulated at several levels, including DNA transcription; mRNA translation and stability; and protein trafficking. This project is focused on whether individual differences in the Tissue Factor gene 3’ untranslated region (UTR) exist that may influence eventual Tissue Factor expression, and hence affect risk of thrombosis.
The 3’UTR of any mRNA influences the translation and stability of the gene, as well as the fate of the gene product. The 3’UTR operates via interactions with RNA-binding proteins, one of which is Human Antigen R (HuR). HuR is able to bind the Tissue Factor mRNA at four discrete U-rich sites (URE-1,2,3,4). We are particularly interested in URE-1, which emerged in evolution about 35 million years ago with the insertion of an Alu transposon and is present in Old World primates and apes but not New World primates. URE-1 is situated at the 5’ point of insertion of the Alu element. Judging from a preliminary assessment of available Old World primate and human species, URE-1 consists of a variable number of Us, ranging from 8-39. As we have experimental evidence that the number of Us affects HuR binding, this variability in URE-1 may be an important influence affecting predisposition to thrombosis.
This will be a bioinformatic project aimed at substantiating individual differences in the number of Us that constitute the URE-1 site, and examining geographical and population variation. If time allows, the project can look at the links between the URE-1 length and disease (eg cardiovascular disease, cancer).
The student will retrieve large-scale genomics data from primates and human populations (including ancient samples) and build models to assess any differentiation and stratification of genetics variation in Tissue Factor 3’ UTR. The student will then investigate clinical database to assess any phenotypic effects of such genetic polymorphisms.
Additional requirements
A background in biological sciences is desirable. A good attitude to coding and data analysis is essential. The student will be co-supervised by Professor Dorian Haskard from the National Heart & Lung Institute.
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