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Evolutionary genomics: new perspectives and novel medical applications

Evolutionary genomics: new perspectives and novel medical applications

Objective

To make for better diagnostics and safer applications of genomics we need a better understanding of our genome and how it functions. Until recently we thought we knew: intergenic sequence must be largely “junk” and mutations that, for example, affect genes but not the protein (synonymous mutations) must be effectively neutral. This degenerate genome view accords with the nearly-neutral theory’s prediction that selection will be weaker when populations are small. But is this all there is to it? I shall investigate two new interrelated perspectives on genome evolution. First, I suggest that to mitigate errors, owing to our high error rates, our genome can be under stronger, not weaker, selection. Second, that errors might be a source of evolutionary novelty. Error mitigation, my team has shown, often involves selection on seemingly innocuous mutations such as synonymous changes. Remarkably, we discovered that selection to ensure error-proof splicing is possibly more prevalent on synonymous mutations when populations are small, making seemingly innocuous mutations stronger candidates for human diseases. I shall provide the first test of the new error-proofing perspective through comparative genomic analysis on synonymous site evolution. To investigate error as a source of novelty I shall consider whether expression piggy-backing (expression of a gene affecting its neighbors) forces rewiring of gene networks. Importantly, I shall translate our new understanding to enable better diagnostics and improved therapeutics. I shall develop a much-needed computer package to identify candidate disease-causing synonymous changes. In addition, knowing how synonymous sites modulate splicing will allow me to design better intronless transgenes. Transgenes must also be inserted in genomic regions immune to piggy-backing. I will examine transposable element related piggy-backing to characterize “safe” sites for therapeutic gene insertion and mammalian transgenesis more generally.
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Host institution

UNIVERSITY OF BATH

Address

Claverton Down
Ba2 7ay Bath

United Kingdom

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 2 260 496

Beneficiaries (3)

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UNIVERSITY OF BATH

United Kingdom

EU Contribution

€ 2 260 496

MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)

Germany

EU Contribution

€ 100 000

THE UNIVERSITY OF EDINBURGH

United Kingdom

EU Contribution

€ 137 500

Project information

Grant agreement ID: 669207

Status

Ongoing project

  • Start date

    1 January 2016

  • End date

    31 December 2020

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 2 497 996

  • EU contribution

    € 2 497 996

Hosted by:

UNIVERSITY OF BATH

United Kingdom