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.