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Dosage sensitive genes in evolution and disease

Objective

Evolutionary change of gene copy number through gene duplication is a relatively pervasive phenomenon in eukaryotic genomes. However, for a subset of genes such changes are deleterious because they result in imbalances in the cell. Such dosage-sensitive genes have been increasingly implicated in disease, particularly through the association of copy number variants (CNVs) with pathogenicity.

In my lab we have previously discovered that many genes in the human genome which were retained after whole genome duplication (WGD) are refractory to gene duplication both over evolutionary timescales and within populations. These are expected characteristics of dosage-balanced genes. Many of these genes are implicated in human disease. I now propose to take a computational (dry-lab) approach to examine the evolution of dosage-balanced genes further and to develop a sophisticated model of evolutionary constraint of copy number. These models will enable the identification of dosage-balanced genes and their consideration as novel candidate disease loci.

Recognising and interpreting patterns of constraint is the cornerstone of molecular evolution. Through careful analysis of genome sequences with respect to gene duplication over evolutionary times and within populations, we will develop a formal and generalised model of copy-number evolution and constraint. We will use these models to identify candidate disease loci within pathogenic CNVs. We will also study the characteristics of known disease genes in order to identify novel candidate loci for dosage-dependent disease.

This is an ambitious and high impact project that has the potential to yield major insights into gene copy-number constraint and its relationship to complex disease.

Field of science

  • /natural sciences/biological sciences/genetics and heredity/genome
  • /natural sciences/biological sciences/molecular biology/molecular evolution

Call for proposal

ERC-2012-StG_20111109
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Address
College Green
2 Dublin
Ireland
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 358 534
Principal investigator
Aoife Mclysaght (Prof.)
Administrative Contact
Deirdre Savage (Ms.)

Beneficiaries (1)

THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Ireland
EU contribution
€ 1 358 534
Address
College Green
2 Dublin
Activity type
Higher or Secondary Education Establishments
Principal investigator
Aoife Mclysaght (Prof.)
Administrative Contact
Deirdre Savage (Ms.)