Featured Papers

Affinity-optimizing enhancer variants disrupt development

Our recent paper published Nature – full article can be found Here

The majority of sequence variants associated with phenotypic variation and disease are location within enhancers. Yet, we don’t know what changes within an enhancer will have an impact on a person or organism and which are simply inert sequence changes.

In this paper we show that enhancers are littered with low-affinity binding sites. Single nucleotide changes within enhancers that increase binding affinity can alter gene expression and cellular identity.

Within mice and humans, we find single-nucleotide changes that increase binding affinity for the transcription factor ETS and Hox transcription factors even slightly cause extra digits. Greater increases in affinity lead to even more extra digits and limb defects.

Within the enhanceosome, single nucleotide variants that increase binding affinity for the transcription factor IRF cause gain of function gene expression.

Across thousands of different enhancers and cell types, we find that affinity-optimizing variants for a variety of transcription factors drive GOF gene expression.

The prevalence of low-affinity binding sites within enhancers creates a vulnerability in genomes whereby single nucleotide variants that optimize binding affinity, even slightly, can be pathogenic. Searching for affinity-optimizing SNVs within the genome provides a mechanistic approach to pinpoint causal enhancer variants that underly diseases.

Affinity-optimizing enhancer variants can cause an extra beating heart

Our recent paper published in Development Cell – Full article can be found Here

In this article we find that low-affinity binding sites are necessary for precise gene expression during heart development. Single-nucleotide changes that increase binding for ETS transcription factors cause ectopic expression, cell migration defects and phenotypes as severe as an extra beating heart!

Within humans, we find developmental heart enhancers contain low-affinity ETS binding sites and the majority of these enhancers are vulnerable to single-nucleotide changes which increase binding affinity. One such enhancer is the human GATA4 enhancer. Single nucleotide changes that increase ETS binding within this enhancer results in gain of function gene expression in human cardiomyocytes.

Affinity-optimizing variants within developmental heart enhancers may contribute to the evolution of multichambered hearts, congenital heart defects and disease.