Combining information about proteins and genes to improve disease insights

29 November 2012

Gene mutations are directly linked to a change in length of the yeast cells.

Image: Gene mutations are directly linked to a change in length of the yeast cells.

Scientists have come up with a new way to study the effects of small gene mutations on cells, providing a simpler, less costly way to study complex diseases that result from many such mutations.

The new approach involves using information about the structures of proteins involved, formulating mathematical models and comparing these with experimental data about the mutations.

DNA provides the genetic instructions for almost all living organisms. This genetic information is transmitted into the cell by being translated into proteins that enable the cell to carry out its functions. These proteins are made from strings of amino acids which are folded into different shapes depending on the amino acid sequence.

Missense mutations are small changes in a genome that alter one amino acid in a protein sequence. They can have a large impact on a cell's behaviour. Because of this, many studies have been carried out assessing missense mutations by directly analysing their impact on proteins - an approach that's useful for working out whether a specific mutation is likely to cause disease.

However missense mutations often occur in combination with other mutations in complex biological pathways, which are difficult for researchers to study.

Paul Bates and his team at Cancer Research UK's London Research Institute (now part of the Francis Crick Institute), along with colleagues from the Universities of Oxford and Cambridge and the Max Planck Institute for Dynamics and Self-Organization in Germany, explored a new way of addressing the problem.

Dr Bates explained: "Advances in technologies known as high-throughput sequencing and microarrays, which allow us to test thousands of genes and mutations very quickly, have significantly increased the pace of detecting mutations in genes and have allowed us to measure gene expression levels on a genome-wide scale. This enables us to analyse complex networks and study entire biological systems.

"In parallel, protein structures are being determined at an ever-increasing rate - many thousands are now publicly available. But little thought has been given to the application of protein structures in conjunction with the missense mutations identified in the high-throughput data, to model behaviour inside cells."

The scientists therefore did just that. They used two biological systems as models to benchmark their approach. The first, fission yeast, has been widely used as a model organism for molecular biology research. It is a well-defined system in which gene mutations are directly linked to a change in length of the yeast cells, making it a straightforward system to study.

The second was a well known human biological pathway called MAPK, which regulates many different cell functions. The MAPK pathway is more complex, with mutations spread within four different proteins that lead to different subtypes of developmental disorders affecting the nervous and circulatory systems, face and skin.

Dr Bates concluded: "Our research suggests that it makes sense to combine multi-level knowledge to investigate the effects of missense mutations on cellular behaviour.

"This approach provides an efficient mechanism for pre-screening the impact of gene mutations in a cost-effective way. It will be particularly useful for studying the causes of complex diseases that usually result from multiple accumulating mutations."

The article, A structural systems biology approach for quantifying the systemic consequences of missense mutations in proteins, is published in PLOS Computational Biology.

 

  • Combining data about small gene mutations with knowledge about relevant protein structures offers a more effective approach to study complex diseases that result from many such mutations.
  • The method makes sense due to improving technologies for screening thousands of gene mutations at a time, as well as protein structures being determined faster, with many thousands already publicly available.
  • Scientists at Cancer Research UK's London Research Institute developed this novel approach and benchmarked it against two model systems - a type of yeast and a well known biological pathway in humans.