Previously unknown functions of genes uncovered

Despite decades of research, the function of many genes is still unknown. This limits our understanding of certain, sometimes rare, diseases and makes it difficult to develop new therapies. In the case of yeast and bacterial cells, there is also a lack of fundamental knowledge for the development of new antimycotics or antibiotics, which are urgently needed due to increasing drug tolerance and resistance. The current study is one of the most comprehensive proteome studies worldwide. The research team analysed yeast cells in more detail in order to better understand the role of genes that have not yet been assigned a precise function. The aim was to obtain crucial information that would allow conclusions to be drawn about the effects of genetic mutations and help to close diagnostic gaps. The researchers wanted to reveal how certain proteins are produced and regulated in detail, not least in order to lay the foundation for the development of new drugs.

Head of research Prof Dr Markus Ralser, Director of the Institute of Molecular Biology at the University of Freiburg. Markus Ralser, Director of the Institute of Biochemistry and Einstein Professor of Biochemistry at the Charité, explains: „We used a collection of yeast strains generated by an international consortium in which all non-essential genes were missing in at least one strain. We used mass spectrometry, a technology that can identify thousands of proteins in parallel, to characterise each of these strains. This ultimately led to this largest proteome study to date." The researchers were able to identify general principles that underlie the production of proteins. For a large number of proteins, the study was able to determine the extent to which their function or biophysical properties are important for production. In the course of the investigations, extensive data on previously little-researched proteins was obtained. At the same time, the team was able to develop new methods for assigning gene functions.

The quantities of the respective proteins in the individual yeast strains were determined in the absence of all non-essential genes using mass spectrometry, in particular special proteome techniques that Prof Ralser and his team have developed in recent years. The findings have the potential to fundamentally improve our understanding of cell biology and provide new insights into gene function in organisms whose cells have a nucleus, so-called eukaryotes," says Dr Georg Kustatscher, who analysed and summarised the huge amount of data from the study with his research group at the University of Edinburgh: „The proteomes that we were able to map in the study contain important information for potential new drug targets that give hope for future treatment options.“

A collaboration between research teams at Charité, the Francis Crick Institute in London and the University of Edinburgh made the comprehensive study possible. Laboratories in Cambridge and at the University of Toronto also contributed. Novel proteome technologies and methods of functional genomics were developed here and used in the study. Prof. Dr Christoph Messner, now group leader at the University of Zurich, was responsible for the work at the Francis Crick Institute in London and emphasises: "To our surprise, the study showed that the response of a protein to any mutation depends more on its biophysical properties than on its function. This opens up a new perspective when analysing large biological data, which is already frequently collected using modern sequencing or mass spectrometry techniques, but is often still difficult to interpret." For this reason, the researchers assume that the results of the present work will have far-reaching implications in the field of biosciences.

The study provides essential information about the function of genes and the formation of proteins. It paves the way for future breakthroughs in the field of microbiology. The team is currently preparing a similar study on human cells with the aim of generating further information on as yet unknown genes. The researchers also want to link the proteome maps created on yeasts with other molecular data in order to help find better therapies for fungal diseases.

*Messner CB et al. The proteomic landscape of genome-wide genetic perturbations. Cell 2023. doi: 10.1016/j.cell.2023.03.026

Mass spectrometry
Mass spectrometry is a technical method for analysing the mass of molecules and atoms. The substance to be analysed is transferred into a gas phase and then ionised. The resulting ions are strongly accelerated using an electric field and sorted in the mass spectrometer's analysis unit according to the ratio of their mass to their charge. The mass spectrum of a substance provides information about its molecular composition. Mass spectrometry is therefore suitable for identifying, characterising and quantifying a variety of biomolecules, such as proteins, metabolites, sugars and fats, which behave differently depending on the disease and the individual.

&about the study
Part of the work was funded by a collaboration between academia and industry, including a mass spectrometer manufacturer (Sciex) and the Biotechnology and Biological Sciences Research Council (BBSRC) in London. Further support was provided by the Wellcome Trust as part of an Investigator Award and the European Research Council with a Synergy Grant.

Article from "Informationsdienst Wissenschaft" from 28 April 2023