Critical genes unravelled to understand human diseases and support drug discovery

06 December 2016

A network analysis of proteins that are most important in responding to environmental signals highlights potential targets for drugs and provides better information on the genetic basis of diseases.

Throughout evolutionary history, there have been genetic elements that have duplicated - giving rise to genes with different functions. These are called ‘paralogs’. They are able to form and evolve new functions, which have similar functions in relation to cellular signalling. This also means that there are many duplicated genes within the genome that might be redundant or less prominent when it comes to key cellular signalling pathways.

Scientists in the UK and Hungary, led by Earlham Institute (EI), have discovered which proteins are critical in a range of biological functions, including cellular communication.

The team found 75 so-called critical paralog groups (CPGs) containing proteins with close evolutionary relationship to each other. One or two members in these groups can be critically important for a specific function, and also their changes, called mutations, can cause cancer or other inherited diseases. 

The systematic discovery of these proteins identifies their indispensable role in human cellular signalling pathways, as well as how to potentially guide drug targets and find biomarkers for disease diagnosis in the future.

Lead author Tamas Korcsmaros, Fellow at EI and the Institute of Food Research, said: “Our cells must be able to detect and respond to many different pieces of genetic information coming from both internal and external sources. However, not all proteins in the cell are equally important. 

In the post-genomic era, we already know there are key groups of proteins responsible for detecting, transmitting and communicating through cross-talk between different cellular pathways. Previously, it was challenging to identify which proteins, in which group, are more critical for the overall function of the cell; and those that are more relevant in causing diseases such as cancer, diabetes or neurodegenerative disorders. 

The computational biology workflow we developed and confirmed with known examples provides an easily applicable method for disease-specific analysis. The concept will also help us to understand fundamental biological questions in comparative genomics on how duplication in the course of evolution led to more complex organs (such as the brain) and organisms.”

First author Dezső Módos, Research Associate at the University of Cambridge, added: “Our study shows the importance of similar proteins (paralogs) in signalling networks. Taking into account the paralog specificity in drug discovery because different paralog-specific signal routes could lead to totally different results like cell death or proliferation."

The paper titled: "Identification of critical paralog groups with indispensable roles in the regulation of signalling flow" is published in Scientific Reports. DOI:10.1038/srep38588.

Notes to editors

For more information, please contact:

Hayley London

Marketing & Communications Officer, Earlham Institute (EI)

  • +44 (0)1603 450 107

hayley.london@earlham.ac.uk

Top image shows: Critical paralogs (CP) can conduct the same incoming signal to different cellular responses like cell-death, differentiation, or cell proliferation through cross-talks between signalling pathways. Paralog proteins (PP) are similar to each other and they act very similarly to signals. In drug development, you have to target one critical paralog to reach a specific signal, meanwhile, you have to target all paralog proteins to have a response. Therefore, distinguishing the two paralog types is crucial to identify and rank drug targets.

The Earlham Institute (EI) is a world-leading research institute focusing on the development of genomics and computational biology. EI is based within the Norwich Research Park and is one of eight institutes that receive strategic funding from Biotechnology and Biological Science Research Council (BBSRC) - £6.45M in 2015/2016 - as well as support from other research funders. EI operates a National Capability to promote the application of genomics and bioinformatics to advance bioscience research and innovation.

EI offers a state of the art DNA sequencing facility, unique by its operation of multiple complementary technologies for data generation. The Institute is a UK hub for innovative bioinformatics through research, analysis and interpretation of multiple, complex data sets. It hosts one of the largest computing hardware facilities dedicated to life science research in Europe. It is also actively involved in developing novel platforms to provide access to computational tools and processing capacity for multiple academic and industrial users and promoting applications of computational Bioscience. Additionally, the Institute offers a training programme through courses and workshops, and an outreach programme targeting key stakeholders, and wider public audiences through dialogue and science communication activities.

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