Phylogeny of functional sequence elements in virus genomes

Viral phylogenies are commonly built from selected open reading frames (ORFs) or genes and ignore recent discoveries on viral genome complexity from functional genomics (omics) studies on virus-infected cells. These omics studies use RNA-seq, Ribo-seq, SHAPE-seq or other sequencing-based assays and vastly extended our knowledge on viral genomes by detecting numerous novel functional sequence elements (FSEs). However, these studies commonly ignore one fundamental question: Are these novel FSEs conserved during virus evolution and thus likely to play an important role in the virus life cycle?
FSEs identified in omics studies include short ORFs (sORFs) with <100 nucleotides, e.g., upstream ORFs (uORFs) within 5’ untranslated regions (UTRs) of other ORFs, or alternative proteins generated from the same locus through programmed ribosomal frameshifting or alternative splicing. In addition, novel viral non-coding RNAs like circular RNAs (circRNAs) and microRNAs (miRNAs) have been discovered. Furthermore, binding sites of host RNA and DNA binding proteins in viral DNA or RNA can now be determined at large scale. These FSEs cannot be predicted from sequence alone and some FSEs have to form specific RNA structures to be functional. To date, no standardised, comprehensive tool is available to detect different types of viral FSEs from omics data and analyse their conservation; existing phylogenetics approaches focus only on protein- genes.

Tools developed in this project combine phylogenetic analyses to characterise the evolution of FSEs with the detection of previously unknown FSEs from omics data to obtain improved robust virus phylogenies.

In this project, we will close this gap by developing tools to identify FSEs that are conserved in sequence and/or structure for (1) reconstructing their evolutionary histories; (2) incorporating them into robust virus phylogenies; and (3) predicting potential functional roles. As recombination is an important evolutionary process that affects many viruses, we will implement a method for recombination-aware reconstruction of phylogenies. We will therefore contribute to central goals G1, G2, and G3 of the CRC VirusREvolution. Our tools will initially be developed for SARS-CoV-2, vibriophage N4, HBV, and HSV-1 and will be generalised to other viruses in subsequent funding phases. Here, inclusion of ancient HBV and HSV-1 genomes and recombination events will also enable us to describe the evolutionary histories of viruses spanning several thousand years. Genome annotations extended with conserved FSEs will be incorporated into VirJenDB within NFDI4Microbiota.

  • WP 1: Identification of functional sequence elements (Friedel)
  • WP 2: Evolutionary history of functional sequence elements (Kühnert)
  • WP 3: Quantifying conservation of functional sequence elements (Kühnert)
  • WP 4: Evaluating functional roles and impact of sequence variation for FSEs (Friedel)

Team Members

Prof. Dr. Caroline Friedel

Project Leader

Dr. Denise Kühnert

Project Leader

N. N.

Doctoral Researcher

N. N.

Doctoral Researcher

Dr. Jens-Uwe Ulrich

Associated Postdoctoral Researcher

Project-Specific Publications

2025

Daodu, Richard Olumide; Awotoro, Ebenezer; Ulrich, Jens-Uwe; Kühnert, Denise

CLASV: Rapid Lassa virus lineage assignment with random forest. Journal Article

In: PLoS Negl Trop Dis, vol. 19, iss. 9, pp. e0013512, 2025, ISSN: 1935-2735.

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2024

Gomez, Luis Roger Esquivel; Weber, Ariane; Kocher, Arthur; Kühnert, Denise

Recombination-aware phylogenetic analysis sheds light on the evolutionary origin of SARS-CoV-2. Journal Article

In: Sci. Rep., vol. 14, iss. 1, pp. 541, 2024, ISSN: 2045-2322.

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2023

Djakovic, Lara; Hennig, Thomas; Reinisch, Katharina; Milić, Andrea; Whisnant, Adam W; Wolf, Katharina; Weiß, Elena; Haas, Tobias; Grothey, Arnhild; Jürges, Christopher S; Kluge, Michael; Wolf, Elmar; Erhard, Florian; Friedel, Caroline C; Dölken, Lars

The HSV-1 ICP22 protein selectively impairs histone repositioning upon Pol II transcription downstream of genes. Journal Article

In: Nat Commun, vol. 14, iss. 1, no. 1, pp. 4591, 2023, ISSN: 2041-1723.

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2021

Smith, Maureen Rebecca; Trofimova, Maria; Weber, Ariane; Duport, Yannick; Kühnert, Denise; Kleist, Max

Rapid incidence estimation from SARS-CoV-2 genomes reveals decreased case detection in Europe during summer 2020. Journal Article

In: Nat Commun, vol. 12, iss. 1, no. 1, pp. 6009, 2021, ISSN: 2041-1723.

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Kocher, Arthur; Papac, Luka; Barquera, Rodrigo; Key, Felix M; Spyrou, Maria A; Hübler, Ron; Rohrlach, Adam B; Aron, Franziska; Stahl, Raphaela; Wissgott, Antje; Bömmel, Florian; Pfefferkorn, Maria; Mittnik, Alissa; Villalba-Mouco, Vanessa; Hansen, Svend; Kitov, Egor P; Dobeš, Miroslav; Ernée, Michal; Meller, Harald; Alt, Kurt W; Prüfer, Kay; Warinner, Christina; Schiffels, Stephan; Stockhammer, Philipp W; Bos, Kirsten; Posth, Cosimo; Herbig, Alexander; Haak, Wolfgang; Krause, Johannes; Kühnert, Denise

Ten millennia of hepatitis B virus evolution. Journal Article

In: Science, vol. 374, iss. 6564, no. 6564, pp. 182–188, 2021, ISSN: 1095-9203.

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2020

Whisnant, Adam W; Jürges, Christopher S; Hennig, Thomas; Wyler, Emanuel; Prusty, Bhupesh; Rutkowski, Andrzej J; L'hernault, Anne; Djakovic, Lara; Göbel, Margarete; Döring, Kristina; Menegatti, Jennifer; Antrobus, Robin; Matheson, Nicholas J; Künzig, Florian W H; Mastrobuoni, Guido; Bielow, Chris; Kempa, Stefan; Liang, Chunguang; Dandekar, Thomas; Zimmer, Ralf; Landthaler, Markus; Grässer, Friedrich; Lehner, Paul J; Friedel, Caroline C; Erhard, Florian; Dölken, Lars

Integrative functional genomics decodes herpes simplex virus 1 Journal Article

In: Nat Commun, vol. 11, iss. 1, pp. 2038, 2020.

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2018

Kühnert, Denise; Kouyos, Roger; Shirreff, George; Pečerska, Jūlija; Scherrer, Alexandra U; Böni, Jürg; Yerly, Sabine; Klimkait, Thomas; Aubert, Vincent; Günthard, Huldrych F; Stadler, Tanja; Bonhoeffer, Sebastian; Study, Swiss HIV Cohort

Quantifying the fitness cost of HIV-1 drug resistance mutations through phylodynamics. Journal Article

In: PLoS Pathog, vol. 14, iss. 2, no. 2, pp. e1006895, 2018, ISSN: 1553-7374.

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Hennig, Thomas; Michalski, Marco; Rutkowski, Andrzej J; Djakovic, Lara; Whisnant, Adam W; Friedl, Marie-Sophie; Jha, Bhaskar Anand; Baptista, Marisa A P; L'Hernault, Anne; Erhard, Florian; Dölken, Lars; Friedel, Caroline C

HSV-1-induced disruption of transcription termination resembles a cellular stress response but selectively increases chromatin accessibility downstream of genes. Journal Article

In: PLoS Pathog, vol. 14, iss. 3, no. 3, pp. e1006954, 2018, ISSN: 1553-7374.

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2017

Bonfert, Thomas; Friedel, Caroline C

Prediction of poly(A) sites by poly(A) read mapping. Journal Article

In: PLoS One, vol. 12, iss. 1, no. 1, pp. e0170914, 2017, ISSN: 1932-6203.

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2015

Rutkowski, Andrzej J; Erhard, Florian; L'Hernault, Anne; Bonfert, Thomas; Schilhabel, Markus; Crump, Colin; Rosenstiel, Philip; Efstathiou, Stacey; Zimmer, Ralf; Friedel, Caroline C; Dölken, Lars

Widespread disruption of host transcription termination in HSV-1 infection. Journal Article

In: Nat Commun, vol. 6, pp. 7126, 2015, ISSN: 2041-1723.

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