Every organism\u2019s genome contains mutations that often have unknown biological effects. In partnership with Stanford University (USA), researchers at Charit\u00e9 \u2013\u00a0Universit\u00e4tsmedizin Berlin\u00a0have now discovered a way to predict the effects of numerous mutations in yeast. Key to this discovery was a detailed analysis of the proteome \u2013 the collection of all proteins inside a cell. The research team believe this new method to be a valuable tool for better understanding molecular mechanisms, for example, in the context of microorganisms\u2019 increasing resistance to medicinal agents. The study has been published in the Science\u00a0journal.\u00a0<\/p>\n
Microorganisms are masters of adaptation. Even the smallest of genetic variations can help them adapt to changing, and sometimes hostile, conditions in their habitat. That includes, for example, developing resistance to medicinal agents. \u201cTo be able to better assess the risk of a pathogen becoming resistant, or to develop new and improved agents, we need to learn to better understand the association between different gene variants and their resulting biological mutations,\u201d says Prof. Markus Ralser, Director of the Institute of Biochemistry at Charit\u00e9 and one of the two study leads. \u201cSince genome sequencing has advanced so rapidly, we can identify genetic differences very well nowadays. However, we often do not know their impact on a microbe\u2019s growth or resistance, for example, or under which conditions they are significant.\u201d\u00a0\u00a0<\/p>\n
A glimpse into the molecular blackbox<\/p>\n
To understand the effects of different gene variants, it helps to take a look at the proteome. The proteome works like a kind of gear train that controls and conducts cellular processes, keeping everything running. The various proteins interlock, almost like cogs, and influence each other. \u201cFor example, a specific variant in a gene can mean that a protein is no longer produced, or is produced in a different form or quantity. And that can actually change quite a lot in the cell\u2019s inner workings,\u201d says Dr. Johannes Hartl of the Berlin Institute of Health at Charit\u00e9 (BIH) and one of the lead authors of the study. \u201cAs its natural genetic variation causes it to be so variable, the proteome is still largely a molecular blackbox. Our study was able to show that it was both possible and necessary to shine more light into this darkness.\u201d<\/p>\n
The researchers used two naturally occurring strains of yeast cells for their investigation. Yeasts are single-celled microorganisms belonging to the fungi kingdom. One of the yeast strains came from a Californian vineyard, while the other was isolated from an immunosuppressed patient in Italy. The researchers crossbred the two strains over multiple generations. \u201cThis created almost a thousand new yeast strains, in which the parents\u2019 genetic features were thoroughly mixed,\u201d explains Johannes Hartl. The crossbreeding experiments and subsequent genetic analysis of the yeast strains were carried out in the laboratory at Stanford. The Charit\u00e9 team led by Markus Ralser analysed the proteome of the different strains using a high-throughput screening process and mass spectrometry. This allowed them to clearly identify different proteins and precisely quantify their respective amounts in the cell.\u00a0<\/p>\n
Proteome reveals molecular basis<\/p>\n
Together, the researchers worked through the vast treasure trove of data. The goal: to find clear associations between the individual gene variants and the resulting changes in the proteome. \u201cTo achieve this, we compared the genome and proteome data and created a kind of map that shows the effect of thousands of genetic variants on the amount of thousands of proteins in the cell,\u201d Johannes Hartl explains. \u201cAnd to check whether the associations we found actually stemmed from this particular gene variant, and not from other processes within the cell, for example, we used the CRISPR\/Cas \u2018genetic scissors\u2019 to insert the gene variant into the original parent strain of the yeast, which did not previously contain this gene variant. We then looked to see if the corresponding changes in the proteome could also be found here.\u201d\u00a0<\/p>\n
The researchers went one step further with some gene variants and the associated changes in the proteome, and they examined their specific effects. For example, they investigated whether the yeast cells could survive under the effects of an antimycotic agent \u2013 also known as an antifungal drug. \u201cThe antmycotic agent binds to and inhibits an enzyme that is necessary for the biosynthesis of an essential part of the yeast membrane. This stops the cell from continuing to grow \u2013 provided that the agent blocks enough of the present enzymes,\u201d says Johannes Hartl. \u201cIn our genome-to-proteome map, however, we were able to see that certain gene variants contained raised levels of this enzyme. The experiment showed that yeast cells with this gene variant became more resistant to the antimycotic agent.\u201d<\/p>\n
Small genetic mutations can have a significant impact<\/p>\n
The study also showed that many genetic changes \u2013 even those that seem \u201cunremarkable\u201d at first glance \u2013 can have far-reaching consequences. The researchers observed that genetic variants affecting hundreds of proteins in the cell had no apparent effect under standard conditions. However, when those conditions were altered, such as through drug treatment or changes in nutrient supply, those variants had a significant impact on cell growth.<\/p>\n
\u201cThe genome-to-proteome map is an outstanding tool for revealing associations in molecular biology and understanding the impact of mutations and genetic differences,\u201d Markus Ralser emphasizes. \u201cAs a result, it is now much easier for us to figure out many of the proteins\u2019 functions and interactions, which enables us to better predict how they may potentially develop resistances to agents and adapt to new environments, like humans as host organisms.\u201d In subsequent studies, the researchers therefore wish to extend this approach to fungal pathogens that cause particularly severe infections in humans.<\/p>\n
Reference:\u00a0<\/b>Jakobson CM, Hartl J, Tr\u00e9bulle P, M\u00fclleder M, Jarosz DF, Ralser M. A genome-to-proteome map reveals how natural variants drive proteome diversity and shape fitness. Science. 2025;390(6769):eadu3198. doi:\u00a010.1126\/science.adu3198<\/a><\/p>\n This article has been republished from the following materials<\/a>. Note: material may have been edited for length and content. For further information, please contact the cited source. Our press release publishing policy can be accessed here<\/a>.<\/p>\n","protected":false},"excerpt":{"rendered":"Every organism\u2019s genome contains mutations that often have unknown biological effects. In partnership with Stanford University (USA), researchers…\n","protected":false},"author":3,"featured_media":299523,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[26],"tags":[815,159,67,132,68],"class_list":{"0":"post-299522","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-genetics","8":"tag-genetics","9":"tag-science","10":"tag-united-states","11":"tag-unitedstates","12":"tag-us"},"share_on_mastodon":{"url":"https:\/\/pubeurope.com\/@us\/115366051378962648","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts\/299522","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/comments?post=299522"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/posts\/299522\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/media\/299523"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/media?parent=299522"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/categories?post=299522"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/us\/wp-json\/wp\/v2\/tags?post=299522"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}